Tricyclic spiro compound

ABSTRACT

A medicinal agent for the prevention and/or treatment of diseases caused by EP 4  receptor activation. A compound having antagonistic activity against the EP 4  receptor is contained as an active ingredient in the medicinal agent. The compound represented by the following general formula (I) as defined in the specification, a salt, an N-oxide, or a solvate thereof, or a prodrug of these is useful as a medicinal component having antagonistic activity against the EP 4  receptor for the prevention and/or treatment of diseases caused by EP 4  receptor activation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Rule 53(b) Continuation of U.S. application Ser.No. 15/542,216 filed Jul. 7, 2017, which is a National Stage Applicationfiled under § 371 of International Application No. PCT/JP2016/050446filed Jan. 8, 2016, claiming priority based on Japanese PatentApplication No. 2015-002712 filed Jan. 9, 2015, the contents of all ofwhich are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to an EP₄ receptor antagonist tricyclicspiro compound or a salt thereof, and to a medicament containing such acompound as an active ingredient. Specifically, the invention relates toa tricyclic spiro compound represented by the following general formula(I), a salt, an N-oxide, or a solvate thereof, or a prodrug of these(hereinafter, these will be referred to as “present compounds”), and toa medicament containing such a compound as an active ingredient.

The symbols used in general formula (I) are as defined below.

BACKGROUND ART

The prostaglandin E₂ (PGE₂), a known metabolite of the arachidonic acidcascade, is known to have a range of effects including cytoprotection,uterine contraction, lowering of the threshold of pain, promotion ofperistalsis in the digestive tract, wakefulness, inhibition of stomachacid secretion, hypotensive effect, and diuretic effect.

Recent studies have found that there are subtypes of PGE₂ receptors withdifferent roles. To date, four broad subtypes are known, and these arecalled EP₁, EP₂, EP₃, and EP₄ (Journal of Lipid Mediators and CellSignalling, Vol. 12, p. 379-391, 1995).

In these subtypes, the EP₄ receptor is thought to be involved ininhibition of MCP-1 production from macrophages, inhibition of TNF-α,IL-2, and IFN-γ production from lymphocytes. This subtype is alsobelieved to have involvement in anti-inflammation by enhanced IL-10production, vasodilatation, angiogenesis, inhibition of elastic fiberformation, and regulation of MMP-9 expression. Other possibleinvolvement of the EP₄ receptor includes immune control in cancerviamyeloidderived suppressor cells, regulatory T cells, and naturalkiller cells.

It is therefore thought that compounds that strongly bind to the EP₄receptor, and show antagonistic activity are useful for the preventionand/or treatment of diseases caused by EP₄ receptor activation,including, for example, a bone disease, a cancer, a systemicgranulomatous disease, an immune disease, allergy, atopy, asthma,alveolar pyorrhea, gingivitis, periodontitis, Alzheimer's, Kawasakidisease, burn, multiple organ failure, chronic headache, pain,vasculitis, venous incompetence, varicose veins, aneurysm, aorticaneurysm, anal fistula, diabetes insipidus, stress, endometriosis,uterine adenomyosis, patent ductus arteriosus in neonates, andcholelithiasis (Pharmacological Reviews, Vol. 65, p. 1010-1052, July,2013; 105th Annual Meeting of American Association for Cancer Research(AACR), Abstract: LB-265, Title of Presentation: ONO-AE3-208 InhibitsMyeloid Derived Suppressor Cells and Glioma Growth, Date ofPresentation: Apr. 8, 2014; FEBS Letters, Vol. 364, p. 339-341, 1995;Cancer Science, Vol. 105, p. 1142-1151, 2014; Cancer Research, Vol. 70,p. 1606-1615, 2010; and Cancer Research, Vol. 62, p. 28-32, 2002).

WO02000/020371 describes a compound of the following general formula (A)used for the treatment of diseases involving prostaglandin E receptors,for example, such as pain, inflammation, and cancer.

In the general formula (A),

Ar^(1a) is an aryl or a heteroaryl group optionally substituted withR^(1a) or R^(3a), wherein R^(1a) is CN, NO₂, CON(R^(5a))₂, or the like;

W^(a) represents a three- to six-membered linking group containing 0 to2 heteroatoms selected from O, N, and S, wherein the linking groupoptionally contains CO, S(O)_(na), C═C, or an acetylene group;

Ar^(2a) is an aryl or a heteroaryl group optionally substituted withR^(3a), wherein R^(3a) is halogen, CN, or the like;

X^(a) is a linker attached to Ar^(2a) at the position ortho to thebonding site for W^(a); and

Q^(a) is COOH or the like

(These are only a part of the definitions of the groups.)

WO2003/016254 describes a compound of the following general formula (B)that binds to the PGE₂ receptor, particularly EP₃ and/or EP₄, and hasantagonistic activity, useful for the prevention and/or treatment ofdiseases such as pain, and cancer.

In the general formula (B),

R^(1b) represents —COOH or the like;

A^(b) represents (i) a single bond, (ii) C1-6 alkylene, (iii) C2-6alkenylene, (iv) C2-6 alkynylene, or the like;

the ring B^(b) represents a C3-12 monocyclic or bicyclic carbon ring, ora three- to twelve-membered monocyclic or bicyclic heterocyclic ring;

R^(2b) represents nitro, cyano, or the like;

Q^(b) represents C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl substituted with1 to 3 halogen atoms, cyano, nitro, or the like;

D^(b) is a one- or two-membered linking chain of atoms selected from acarbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, whereinthe linking chain may contain a double bond or a triple bond, and may besubstituted with one to four R^(40b), wherein R^(40b) represents an oxo,halogen, or the like; and

R^(3b) represents (1) C1-6 alkyl, or (2) a C3-15 monocyclic, bicyclic,or tricyclic carbon ring that is substituted with one to five R^(42b),or that is unsubstituted, or a three- to fifteen-membered monocyclic,bicyclic, or tricyclic heterocyclic ring, wherein R^(42b) representsC1-6 alkyl, C1-6 alkoxy, halogen, cyano, —NR^(46b)COR^(47b), orCyc10^(b). (These are only a part of the definitions of the groups.)

WO1999/047497 describes a compound of the following general formula (C)used for the treatment of diseases involving prostaglandin E receptors,for example, such as pain, inflammation, and cancer.

In the general formula (C),

HET^(c) represents a five- to twelve-membered monocyclic or bicyclicaromatic ring system having 0 to 3 heteroatoms selected from O,S(O)_(nc), and N(O)_(mc), wherein mc is 0 or 1, and nc is 0, 1, or 2;

A^(c) is one- or two-atom moiety and is selected from the groupincluding —W^(c)— and —C(O)—, wherein W^(c) is O, S(O)_(nc), orNR^(17c);

X^(c) represents a five- to ten-membered monocyclic or bicyclic aryl orheteroaryl group having 1 to 3 heteroatoms selected from O, S(O)_(nc),and N(O)_(mc),

Y^(c) represents O, S(O)_(nc), NR^(17c), a bond, or the like;

B^(c) is —(C(R^(18c))₂)_(pc)—Y^(c)— (C(R^(18c))₂)_(qc)—, wherein pc andqc are independently 0 to 3;

Z^(c) is OH, or the like; and

R^(1c), R^(2c), and R^(3c) independently represent halogen, —CO₂R^(9c),—CON(R^(6c))₂, or the like.

(These are only a part of the definitions of the groups.)

None of these related art documents describe or suggest the presentcompound, specifically, the tricyclic spiro compound.

CITED REFERENCES Patent Documents

-   PATENT DOCUMENT 1: WO2000/020371-   PATENT DOCUMENT 2: WO2003/016254-   PATENT DOCUMENT 3: WO1999/047497

Non-Patent Documents

-   NON-PATENT DOCUMENT 1: Journal of Lipid Mediators and Cell    Signalling, Vol. 12, p. 379-391, 1995-   NON-PATENT DOCUMENT 2: Pharmacological Reviews, Vol. 65, p.    1010-1052, July, 2013-   NON-PATENT DOCUMENT 3: 105th Annual Meeting of American Association    for Cancer Research (AACR), Abstract: LB-265, Title of Presentation:    ONO-AE3-208 Inhibits Myeloid Derived Suppressor Cells and Glioma    Growth, Date of Presentation: Apr. 8, 2014-   NON-PATENT DOCUMENT 4: FEBS Letters, Vol. 364, p. 339-341, 1995-   NON-PATENT DOCUMENT 5: Cancer Science, Vol. 105, p. 1142-1151, 2014-   NON-PATENT DOCUMENT 6: Cancer Research, Vol. 70, p. 1606-1615, 2010-   NON-PATENT DOCUMENT 7: Cancer Research, Vol. 62, p. 28-32, 2002

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

The present invention is intended to create compounds that have a strongantagonistic activity against the EP₄ receptor, and show desirablepharmacokinetics, and to find a compound that is useful as a preventiveand/or a therapeutic drug for diseases caused by EP₄ receptoractivation.

Means for Solving the Problems

In order to achieve the foregoing object, the present inventorsconducted intensive studies to find a compound that has a strongantagonistic activity against the EP₄ receptor, and shows desirablepharmacokinetics, and found that compounds represented by the generalformula (I) below are a strong antagonist of the EP₄ receptor. Thepresent invention was completed on the basis of this finding.

Specifically, an aspect of the present invention is as follows.

[1] A compound represented by the following general formula (I), or asalt, an N-oxide, or a solvate thereof, or a prodrug of these.

In the general formula (I),

R¹ represents COOR⁸, tetrazole, SO₃H, SO₂NH₂, SO₂NH⁸⁻¹, CONHSO₂R⁸⁻¹,SO₂NHCOR⁸⁻¹, or hydroxamic acid, wherein R⁸ represents a hydrogen atom,C1-4 alkyl, or benzyl, R⁸⁻¹ represents C1-4 alkyl, C1-4 haloalkyl, aC3-10 carbon ring, or a three- to ten-membered heterocyclic ring,wherein the C3-10 carbon ring, and the three- to ten-memberedheterocyclic ring each may be substituted with C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxy, —O(C1-4 haloalkyl), C1-4 alkylthio, —S(C1-4haloalkyl), halogen, or nitrile (here and below, “—CN”),

L¹ represents C1-5 alkylene, C2-5 alkenylene, or C2-5 alkynylene,

R² represents halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C2-4alkenyl, C2-4 alkynyl, —O(C1-4 haloalkyl), —S(C1-4 haloalkyl), —C(O)(C1-4 alkyl), —SO₂(C1-4 alkyl), —CONH(C1-4 alkyl), —CON(C1-4 alkyl)₂,—NHC(O) (C1-4 alkyl), —N(C1-4 alkyl)C(O)(C1-4 alkyl), —NHSO₂(C1-4alkyl), —N(C1-4 alkyl)SO₂(C1-4 alkyl), —SO₂NH(C1-4 alkyl), —SO₂N(C1-4alkyl)₂, —NR¹⁷R¹⁷, nitro, nitrile, a hydroxyl group, aldehyde, orcarboxyl, wherein the C1-4 alkyl each may be substituted with halogen,and wherein the (C1-4 alkyl)₂ represented by R² represents twoindependent C1-4 alkyl groups which may be the same or different,

X¹ represents CR⁶, or a nitrogen atom, wherein R⁶ represents a hydrogenatom, or R²,

X² represents CR⁷, or a nitrogen atom, wherein R⁷ represents a hydrogenatom, R², or -L³-R⁹, wherein L³ represents methylene, an oxygen atom, ora sulfur atom which may be oxidized, and R⁹ represents a four- toten-membered heterocyclic ring which may be substituted with asubstituent selected from the group consisting of halogen, C1-4 alkyl,and C1-4 haloalkyl,

L² represents —CH₂CH₂—, —CH═CH—, —CH₂O—, —OCH₂—, —CH₂S—, —SCH₂—,—CH₂S(O)—, —S(O) CH₂—, —CH₂SO₂—, —SO₂CH₂—, —CH₂NH—, —NHCH₂—, —NHCO—,—CONH—, —NHSO₂—, or —SO₂NH—,

R³ represents C1-4 alkyl, or halogen,

R⁴ represents halogen, C1-4 alkyl, or C1-4 haloalkyl,

X³ represents methylene, an oxygen atom, a sulfur atom which may beoxidized, or NR¹⁰, wherein R¹⁰ represents C1-4 alkyl, —C(O) (C1-4alkyl), —C(O)O(C1-4 alkyl), or —SO₂(C1-4 alkyl), wherein the C1-4 alkyleach may be substituted with halogen,

the ring represents a benzene ring, or a five- to six-memberedmonocyclic aromatic heterocyclic ring,

represents a single bond, or a double bond,

R⁵ represents (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile,(5) —CONHR¹¹, (6) —C(O)R¹², (7) —OR¹⁴, (8) —S(O)_(t)R⁵, (9) —CH₂R¹⁶,(10) —NR¹⁷R¹⁷, (11) —NHCOR¹¹, (12) a C4-10 carbon ring, or (13) a four-to ten-membered heterocyclic ring, wherein the C4-10 carbon ring, or thefour- to ten-membered heterocyclic ring may be substituted with one tothree R¹⁸, wherein, when a plurality of R¹⁸ exists, the plurality of R¹⁸independently may be the same or different, R¹¹ represents C1-6 alkyl,C3-6 cycloalkyl, phenyl, or a four- to six-membered heterocyclic ring,and may be substituted with one to three R¹³, wherein, when a pluralityof R¹³ exists, the plurality of R¹³ independently may be the same ordifferent, R¹³ represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4alkoxy, a hydroxyl group, —NR²⁰R²¹, benzene, or a four- to six-memberedheterocyclic ring, wherein R²⁰ and R²¹ each independently represent ahydrogen atom, or C1-4 alkyl, R¹² represents C1-6 alkyl, C3-6cycloalkyl, benzene, or a four- to six-membered heterocyclic ring,wherein the C3-6 cycloalkyl, the benzene, and the four- to six-memberedheterocyclic ring each independently may be substituted with halogen,C1-4 alkyl, or C1-4 alkoxy, R¹⁴ represents a hydrogen atom, C1-6 alkyl,C3-6 cycloalkyl, benzene, or benzyl, wherein the C1-6 alkyl may besubstituted with one to three R¹⁹, wherein, when a plurality of R¹⁹exists, the plurality of R¹⁹ independently may be the same or different,R¹⁹ represents C1-4 alkoxy, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)₂, or afive- to six-membered monocyclic aromatic heterocyclic ring which may besubstituted with a substituent selected from the group consisting ofC1-4 alkyl, and C1-4 haloalkyl, wherein the (C1-4 alkyl)₂ represented byR¹⁹ represents two independent C1-4 alkyl groups which may be the sameor different, R¹⁵ represents C1-6 alkyl, C3-6 cycloalkyl, benzene, orbenzyl, R¹⁶ represents a hydroxyl group, or C1-4 alkoxy, R¹⁷ eachindependently represent a hydrogen atom, C1-6 alkyl, or C3-6 cycloalkyl,R¹⁸ represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, oxo,nitrile, a hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C1-4alkyl)SO₂—, a four- to six-membered heterocyclic ring, (C1-4 alkyl)NH—,or (C1-4 alkyl)₂N—, wherein the (C1-4 alkyl)₂ represented by R¹⁸represents two independent C1-4 alkyl groups which may be the same ordifferent,

m represents an integer of 1 to 4,

n represents an integer of 0 to 4,

p represents an integer of 0 to 2,

q represents an integer of 0 to 6,

r represents an integer of 0 to 6,

s represents an integer of 0 to 4,

t represents an integer of 0 to 2, and

R², R³, R⁴, and R⁵ each independently may be the same or different whenp, q, r, and s are each an integer of 2 or more.

[2] The compound according to item [1], which is represented by thefollowing general formula (I-1),

wherein na represents an integer of 0 to 1, qa represents an integer of0 to 3, ra represents an integer of 0 to 4, X^(3a) represents methylene,or an oxygen atom, and the other symbols are as defined in item [1].

[3] The compound according to item [1] or [2], wherein at least one R⁵is —CONHR¹¹.

[4] The compound according to any one of items [1] to [3], wherein L² is—NHCO—, or —CONH—.

[5] The compound according to any one of items [1] to [4], which isrepresented by the following general formula (I-2),

wherein R^(2a) represents halogen, R^(6a) represents a hydrogen atom, orhalogen, and the other symbols are as defined in items [1] and [2].

[6] The compound according to item [1], which is any one of thefollowing:

(1)

-   4-[4-cyano-2-({[(2′R,4S)-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(2)

-   4-{4-cyano-2-[({(2′R,4S)-6-[(cyclopropylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(3)

-   4-{4-cyano-2-[({(2′R,4S)-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(4)

-   4-{4-cyano-2-[({(2′R,4S)-6-[(2-methyl-2-propanyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbon    yl)amino]phenyl}butanoic acid,

(5)

-   4-[4-cyano-2-({[(2′R,4S)-6-{[(2S)-1-methoxy-2-propanyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(6)

-   4-{4-cyano-2-[({(2′R,4S)-6-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(7)

-   4-[4-cyano-2-({[(2′R,4S)-6-(cyclopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(8)

-   4-[4-cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(9)

-   4-[4-cyano-2-({[(2′R,4S)-6-(cyclopentylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(10)

-   4-{2-[({(2′R,4S)-6-[(2S)-2-butanylcarbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]-4-cyanophenyl}butanoic    acid,

(11)

-   4-{4-cyano-2-[({(2′R,4S)-6-[(trans-4-hydroxycyclohexyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(12)

-   4-{4-cyano-2-[({(2′R,4S)-6-[(cis-4-hydroxycyclohexyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(13)

-   4-[4-cyano-2-({[(2′R,4S)-6-(2-pyridinylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(14)

-   4-[4-cyano-2-({[(2′R,4S)-6-(3-pyridazinylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(15)

-   4-[4-cyano-2-({[(2′R,4S)-6-(cyclobutylcarbamoyl)-2,3-dihyd    rospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(16)

-   4-[4-cyano-2-({[(2′R,4S)-6-{[1-(2-methyl-2-propanyl)-1H-pyrazol-4-yl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclo    propan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,

(17)

-   4-[4-cyano-2-({[(2′R,4S)-6-(tetrahydro-2H-pyran-4-ylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(18)

-   4-[4-cyano-2-({[(2′R,4S)-6-(propylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(19)

-   4-{4-cyano-2-[({(2′R,4S)-6-[(2-ethoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(20)

-   4-[4-cyano-2-({[(2′R,4S)-6-(ethylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(21)

-   4-[4-cyano-2-({[(1R,2R)-6′-(methylcarbamoyl)-2′,3′-dihydro    spiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoic    acid,

(22)

-   4-{4-cyano-2-[({(1R,2R)-6′-[(2-methoxyethyl)carbamoyl]-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl}carbonyl)amino]phenyl}butanoic    acid,

(23)

-   4-{4-cyano-2-[({(1R,2R)-6′-[(1-methyl-1H-pyrazol-4-yl)carbamoyl]-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl}carbonyl)amino]phenyl}butanoic    acid,

(24)

-   4-[4-cyano-2-({[(2′R,4S)-7-fluoro-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(25)

-   4-{4-cyano-2-[({(2′R,4S)-7-fluoro-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(26)

-   4-[4-cyano-2-({[(2′R,4S)-7-fluoro-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(27)

-   4-[4-cyano-2-({[(2′R,4S)-7-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(28)

-   4-{4-cyano-2-[({(2′R,4S)-7-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(29)

-   4-[4-cyano-2-({[(2′R,4S)-7-methoxy-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(30)

-   4-{4-cyano-2-[({(2′R,4S)-7-methoxy-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(31)

-   4-[4-cyano-2-({[(2′R,3S)-5-(methylcarbamoyl)spiro[1-benzofuran-3,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(32)

-   4-{4-cyano-2-[({(2′R,3S)-5-[(2-methoxyethyl)carbamoyl]spiro[1-benzofuran-3,1′-cyclopropan]-2′-yl}carbonyl)amino]phen    yl}butanoic acid,

(33)

-   4-[4-cyano-2-({[(1S,2R)-6′-[(2-methoxyethyl)carbamoyl]-3′,3′-dimethyl-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoic    acid, and

(34)

-   4-[4-cyano-2-({[(1S,2R)-3′,3′-dimethyl-6′-(methylcarbamoyl)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoic    acid.

[7] The compound according to item [1] or [2], wherein at least one R⁵is a C4-10 carbon ring which may be substituted with one to three R¹⁸,or a four- to ten-membered heterocyclic ring which may be substitutedwith one to three R¹⁸, wherein, when a plurality of R¹⁸ exists, theplurality of R¹⁸ each independently may be the same or different.

[8] The compound according to item [7], wherein L² is —NHCO—, or —CONH—.

[9] The compound according to any one of items [1], [2], [7], and [8],which is represented by the following general formula (I-3),

wherein R^(5a) is a C4-10 carbon ring which may be substituted with oneto three R¹⁸, or a four- to ten-membered heterocyclic ring which may besubstituted with one to three R¹⁸, wherein, when a plurality of R¹⁸exists, the plurality of R¹⁸ each independently may be the same ordifferent, and the other symbols are as defined in items [1], [2], and[5].

[10] The compound according to item [1], which is any one of thefollowing:

(1)

-   4-[4-cyano-2-({[(2′R,4S)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(2)

-   4-[4-cyano-2-({[(2′R,4S)-6-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(3)

-   4-[4-cyano-2-({[(2′R,4S)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(4)

-   4-[4-cyano-2-({[(2′R,4S)-6-(3-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(5)

-   4-[4-cyano-2-({[(2′R,4S)-6-(1H-pyrazol-1-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(6)

-   4-[4-cyano-2-({[(2′R,4S)-6-(1H-pyrazol-5-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(7)

-   4-[4-cyano-2-({[(2′R,4S)-6-(4-pyridazinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(8)

-   4-[4-cyano-2-({[(2′R,4S)-6-(2-oxo-1-pyrrolidinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(9)

-   4-[4-cyano-2-({[(2′R,4S)-6-(6-methoxy-3-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(10)

-   4-{4-cyano-2-[({(2′R,4S)-6-[6-(1H-pyrazol-1-yl)-3-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(11)

-   4-{4-cyano-2-[({(2′R,4S)-6-[6-(dimethylamino)-3-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(12)

-   4-[4-cyano-2-({[(2′R,4S)-6-(6-methyl-3-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(13)

-   4-{4-cyano-2-[({(2′R,4S)-6-[6-(methylamino)-3-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic    acid,

(14)

-   4-[4-cyano-2-({[(2′R,4S)-6-(2-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(15)

-   4-[4-cyano-2-({[(2′R,4S)-6-(1,3-thiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(16)

-   4-[4-cyano-2-({[(2′R,4S)-6-(1,3-oxazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(17)

-   4-[4-cyano-2-({[(2′R,4S)-6-(1-methyl-1H-1,2,3-triazol-4-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbon    yl}amino)phenyl]butanoic acid,

(18)

-   4-[4-cyano-2-({[(2′R,4S)-6-(3-pyridazinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid,

(19)

-   4-[4-cyano-2-({[(2′R,3S)-5-(3-pyridinyl)spiro[1-benzofuran-3,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic    acid, and

(20)

-   4-[4-cyano-2-({[(1S,2R)-3′,3′-dimethyl-6′-(3-pyridinyl)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoic    acid.

[11] A pharmaceutical composition comprising the compound of generalformula (I) according to item [1], a salt, an N-oxide, or a solvatethereof, or a prodrug of these as an active ingredient.

[12] The composition according to item [11], which is an EP₄ receptorantagonist.

[13] The composition according to item [11], which is a preventiveand/or a therapeutic agent against a disease caused by EP₄ receptoractivation.

[14] The composition according to item [13], wherein the disease causedby EP₄ receptor activation is a bone disease, a cancer, a systemicgranulomatous disease, an immune disease, alveolar pyorrhea, gingivitis,periodontitis, Kawasaki disease, multiple organ failure, chronicheadache, pain, vasculitis, venous incompetence, varicose veins,aneurysm, aortic aneurysm, anal fistula, diabetes insipidus, patentductus arteriosus in neonates, or cholelithiasis.

[15] The composition according to item [14], wherein the cancer isbreast cancer, ovarian cancer, colorectal cancer, lung cancer, prostatecancer, head and neck cancer, lymphoma, uveal melanoma, thymoma,mesothelioma, esophageal cancer, stomach cancer, duodenal cancer,hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer,pancreatic cancer, renal cell carcinoma, renal pelvis and ureter cancer,bladder cancer, penile cancer, testicular cancer, uterus cancer, vaginalcancer, vulvar cancer, skin cancer, malignant bone tumor, soft tissuesarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, or multiplemyeloma.

[16] A medicament comprising the compound of general formula (I)according to item [1], a salt, an N-oxide, or a solvate thereof, or aprodrug of these with at least one selected from an alkylating agent, anantimetabolite, an anti-cancer antibiotic, a plant-based preparation, ahormonal agent, a platinum compound, a topoisomerase inhibitor, a kinaseinhibitor, an anti-CD20 antibody, an anti-HER2 antibody, an anti-EGFRantibody, an anti-VEGF antibody, a proteasome inhibitor, an HDACinhibitor, and an immunomodulator.

[17] A medicament comprising the compound of general formula (I)according to item [1], a salt, an N-oxide, or a solvate thereof, or aprodrug of these with at least one selected from an HMG-CoA reductaseinhibitor, an antihypertensive, and a tetracycline antibiotic.

[18] A medicament comprising the compound of general formula (I)according to item [1], a salt, an N-oxide, or a solvate thereof, or aprodrug of these with at least one selected from an N-type calciumchannel inhibitor, a Nitric oxide synthetase (NOS) inhibitor, and acannabinoid-2 receptor stimulating reagent.

[19] A method for preventing and/or treating a disease caused by EP₄receptor activation,

the method comprising administering an effective amount of the compoundof general formula (I) according to item [1], a salt, an N-oxide, or asolvate thereof, or a prodrug of these to a patient in need ofprevention and/or treatment of a disease caused by EP₄ receptoractivation.

[20] The compound of general formula (I) according to item [1], a salt,an N-oxide, or a solvate thereof, or a prodrug of these for preventionand/or treatment of a disease caused by EP₄ receptor activation.

[21] Use of the compound of general formula (I) according to item [1], asalt, an N-oxide, or a solvate thereof for production of a preventiveand/or a therapeutic agent against a disease caused by EP₄ receptoractivation.

Effect of the Invention

The present compound has a strong antagonistic activity against the EP₄receptor, and shows desirable pharmacokinetics. The present compound hasuse as a preventive and/or a therapeutic drug against diseases caused byEP₄ receptor activation.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a diagram representing the anti-tumor effect of the presentcompounds in an allograft model of mouse colorectal cancer cell lineCT26.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

The present invention is described below in detail.

In the present invention, “C1-4 alkyl” is, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or isobutyl.

In the present invention, “C1-3 alkyl” is, for example, methyl, ethyl,n-propyl, or isopropyl.

In the present invention, “C1-5 alkylene” is, for example, methylene,ethylene, propylene, butylene, or pentylene.

In the present invention, “C2-5 alkenylene” is, for example, ethenylene,1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene,1-pentenylene, 2-pentenylene, 3-pentenylene, or 4-pentenylene.

In the present invention, “C2-5 alkynylene” is, for example, ethynylene,1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene,1-pentynylene, 2-pentynylene, 3-pentynylene, or 4-pentynylene.

In the present invention, “halogen” is fluorine, chlorine, bromine, oriodine.

In the present invention, “C1-4 alkoxy” is, for example, methoxy,ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, tert-butoxy, orisobutoxy.

In the present invention, “C1-4 alkylthio” is, for example, methylthio,ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio,tert-butylthio, or isobutylthio.

In the present invention, “C2-4 alkenyl” is, for example, ethenyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, or 3-butenyl.

In the present invention, “C2-4 alkynyl” is, for example, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl.

In the present invention, “C1-4 haloalkyl” representshalogen-substituted C1-4 alkyl, and is, for example, monofluoromethyl,difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl,2,2-difluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl,2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 1,1,2-trifluoroethyl,1,2,2,2-tetrafluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl,1,2-dibromo-1,2,2-trifluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl,3-fluoropropyl, 3-chloropropyl, 2-fluoropropyl, 2-chloropropyl,1-fluoropropyl, 1-chloropropyl, 3,3-difluoropropyl, 2,3-difluoropropyl,1,3-difluoropropyl, 1,2-difluoropropyl, 2,2-difluoropropyl,1,1-difluoropropyl, 3,3,3-trifluoropropyl, 2,3,3-trifluoropropyl,1,3,3-trifluoropropyl, 1,2,2-trifluoropropyl, 1,1,2-trifluoropropyl,1,1,3-trifluoropropyl, 1,1,2,2-tetrafluoropropyl,2,2,3,3,3-pentafluoropropyl, 4-fluorobutyl, 4-chlorobutyl,3-fluorobutyl, 3-chlorobutyl, 2-fluorobutyl, 2-chlorobutyl,1-fluorobutyl, 1-chlorobutyl, 3,3-difluorobutyl, 2,3-difluorobutyl,1,3-difluorobutyl, 1,2-difluorobutyl, 2,2-difluorobutyl,1,1-difluorobutyl, 3,3,3-trifluorobutyl, 2,3,3-trifluorobutyl,1,3,3-trifluorobutyl, 1,2,2-trifluorobutyl, 1,1,2-trifluorobutyl,1,1,3-trifluorobutyl, 1,1,2,2-tetrafluorobutyl, or2,2,3,3,3-pentafluorobutyl.

In the present invention, “sulfur that may be oxidized” representssulfur (S), sulfoxide (S(O)), or sulfone (SO₂).

In the present invention, “four- to ten-membered heterocyclic ring”means a four- to ten-membered monocyclic or bicyclic heterocyclic ringcontaining 1 to 5 heteroatoms selected from an oxygen atom, a nitrogenatom, and a sulfur atom, and is, for example, an oxetane, azetidine,pyrrolidine, pyrrole, imidazole, triazole, tetrazole, pyrazole,pyridine, piperidine, piperazine, pyrazine, pyrimidine, pyridazine,azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran,thiepine, oxazole, isooxazole, thiazole, isothiazole, furazan,oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole,thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole,indolizine, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, indazole, quinoline, isoquinoline, quinolizine,purine, phthalazine, pteridin, naphthyridine, quinoxaline, quinazoline,cinnoline, benzooxazole, benzothiazole, benzoimidazole, benzodioxole,benzooxathiol, chromene, benzofurazan, benzothiadiazole, benzotriazole,pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline,triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, dihydropyrazine,tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine,tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisooxazole, tetrahydroisooxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine,tetrahydrotriazolopyrazine, morpholine, thiomorpholine, oxathiane,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,benzooxathiane, dihydrobenzooxazine, dihydrobenzothiazine,pyrazinomorpholine, dihydrobenzooxazole, perhydrobenzooxazole,dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole,perhydrobenzoimidazole, dioxolan, dioxane, dioxaindan, benzodioxane,thiochromane, dihydrobenzodioxine, dihydrobenzoxathiin, chromane,pyrazolopyrimidine, imidazopyridazine, imidazopyridine,imidazopyrimidine, pyrrolopyridine, pyrrolopyrimidine,pyrrolopyridazine, imidazopyrazine, pyrazolopyridine,pyrazolopyrimidine, triazolopyridine, or dihydropyridooxazine ring.

In the present invention, “three- to ten-membered heterocyclic ring”means a three- to ten-membered monocyclic or bicyclic heterocyclic ringcontaining 1 to 5 heteroatoms selected from an oxygen atom, a nitrogenatom, and a sulfur atom, and is, for example, aziridine, oxirane,thiirane, or any of the heterocyclic rings exemplified above for the“four- to ten-membered heterocyclic ring.”

In the present invention, “five- to ten-membered aromatic heterocyclicring” means a five- to ten-membered monocyclic or bicyclic aromaticheterocyclic ring containing 1 to 4 heteroatoms selected from an oxygenatom, a nitrogen atom, and a sulfur atom, and is, for example, apyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene,oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole,thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene,indazole, purine, benzooxazole, benzothiazole, benzoimidazole,benzofurazan, benzothiadiazole, benzotriazole, quinoline, isoquinoline,phthalazine, pteridin, naphthyridine, quinoxaline, quinazoline, orcinnoline ring.

In the present invention, “five- to six-membered monocyclic aromaticheterocyclic ring” is, for example, a pyrrole, imidazole, triazole,tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan,thiophene, oxazole, isooxazole, thiazole, isothiazole, furazan,oxadiazole, or thiadiazole ring.

In the present invention, “C4-10 carbon ring” means a C4 to 10monocyclic or bicyclic carbon ring, and is, for example, a cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene,perhydroindene, indane, naphthalene, dihydronaphthalene,tetrahydronaphthalene, or perhydronaphthalene ring.

In the present invention, “C3-10 carbon ring” means a C3 to 10monocyclic or bicyclic carbon ring, and is, for example, cyclopropane,or any of the carbon rings exemplified above for the “C4-10 carbonring.”

In the present invention, “C1-6 alkyl” is, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 2-methyl-2-ethylpropyl,1-ethylbutyl, 2-ethylbutyl, or 1,1-dimethylpentyl.

In the present invention, “C3-6 cycloalkyl” is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

In the present invention, “four- to six-membered heterocyclic ring”means a four- to six-membered monocyclic heterocyclic ring containing 1to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom, and is, for example, an oxetane, azetidine, pyrrolidine,piperidine, pyrazine, pyran, thiopyran, oxazine, oxadiazine, thiazine,thiadiazine, pyrrole, imidazole, triazole, tetrazole, pyrazole,pyridine, pyrimidine, pyridazine, furan, thiophene, oxazole, isooxazole,thiazole, isothiazole, furazan, oxadiazole, or thiadiazole ring.

In the present invention, R¹ is preferably COOR⁸.

In the present invention, R⁸ is preferably a hydrogen atom, or C1-4alkyl, more preferably a hydrogen atom.

In the present invention, R⁸⁻¹ is preferably C1-4 alkyl, benzene, orpyridine. The benzene and the pyridine may be substituted with C1-4alkyl, C1-4 haloalkyl, C1-4 alkoxy, —O(C1-4 haloalkyl), C1-4 alkylthio,—S(C1-4 haloalkyl), halogen, or nitrile.

In the present invention, L¹ is preferably C1-5 alkylene, or C2-5alkenylene, more preferably C1-5 alkylene, particularly preferablypropylene.

In the present invention, R² is preferably fluorine.

In the present invention, X¹ is preferably CR⁶.

In the present invention, R⁶ is preferably a hydrogen atom, or fluorine,more preferably a hydrogen atom.

In the present invention, X² is preferably CR⁷.

In the present invention, R⁷ is preferably fluorine, nitrile, —CH₂R⁹, or—OR⁹, more preferably nitrile.

In the present invention, R⁹ is preferably a four- to ten-memberedheterocyclic ring which may be substituted with methyl ortrifluoromethyl. The four- to ten-membered heterocyclic ring ispreferably a five- to ten-membered aromatic heterocyclic ring, morepreferably a five- to ten-membered nitrogen-containing aromaticheterocyclic ring (for example, pyrazole, imidazole, triazole,pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine,imidazopyridazine, imidazopyridine, imidazopyrimidine, imidazopyrazine,pyrazolopyridine, or pyrazolopyrimidine).

In the present invention, L² is preferably —CH═CH—, —NHCO—, —CONH—,—NHSO₂—, or —SO₂NH—, more preferably —NHCO—, or —CONH—, particularlypreferably —NHCO—.

In the present invention, R³ is preferably fluorine.

In the present invention, R⁴ is preferably methyl, ethyl, ortrifluoromethyl, more preferably methyl.

In the present invention, X³ is preferably methylene, or an oxygen atom,more preferably an oxygen atom.

In the present invention, R¹⁰ is preferably methyl, ethyl,methylcarbonyl, ethylcarbonyl, methylsulfonyl, ethylsulfonyl, ortert-butoxycarbonyl.

In the present invention, the ring is preferably a benzene, thiophene,or pyrazole ring, more preferably abenzene ring.

In the present invention, R⁵ is preferably —CONHR¹¹, fluorine, methoxy,a benzene ring, or a four- to ten-membered heterocyclic ring. The four-to ten-membered heterocyclic ring is preferably an azetidine,pyrrolidine, piperidine, oxazolidine, oxadiazole, triazole, thiophene,furan, pyrazole, thiazole, oxazole, imidazole, pyridine, pyrazine,pyridazine, pyrimidine, pyrazolopyrimidine, pyrrolopyrimidine,pyrazolopyridine, pyrrolopyridine, or dihydropyridooxazine ring.

In the present invention, R¹¹ is preferably C1-6 alkyl, C3-6 cycloalkyl,or a pyran, pyrrolidine, piperidine, pyrazole, thiazole, oxazole,isooxazole, pyridine, pyridazine, or pyrimidine ring, more preferablyC1-6 alkyl.

In the present invention, R¹³ is preferably halogen, C1-6 alkyl, C3-6cycloalkyl, C1-4 alkoxy, a hydroxyl group, —NR²⁰R²¹, or a benzene,oxetane, pyridine, pyrazole, or oxazole ring, more preferably fluorine,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,isobutyl, cyclopentyl, cyclobutane, oxetane, a hydroxyl group, methoxy,ethoxy, propoxy, isopropoxy, dimethylamino, or a benzene, pyridine,pyrazole, or oxazole ring.

In the present invention, R²⁰ is preferably a hydrogen atom, or methyl.

In the present invention, R²¹ is preferably a hydrogen atom, or methyl.

In the present invention, R¹² is preferably C1-3 alkyl, C3-6 cycloalkyl,benzene, or a four- to six-membered heterocyclic ring. The four- tosix-membered heterocyclic ring is preferably an oxetane, azetidine,pyrrolidine, piperidine, pyrazine, pyran, thiopyran, oxazine,oxadiazine, thiazine, thiadiazine, pyrrole, imidazole, triazole,tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan,thiophene, oxazole, isooxazole, thiazole, isothiazole, furazan,oxadiazole, or thiadiazole ring. The four- to six-memberedheterocyclicring may be substituted with C1-4 alkoxy.

In the present invention, R¹⁴ is preferably a hydrogen atom, methyl,ethyl, benzene, or benzyl.

In the present invention, R¹⁹ is preferably methoxy, —CONHCH₃,—CON(CH₃)₂, or an oxazole, thiazole, pyrazole, or pyridine ring.

In the present invention, R¹⁵ is preferably methyl, cyclopropyl, orbenzene.

In the present invention, R¹⁶ is preferably a hydroxyl group.

In the present invention, R¹⁷ is preferably methyl, ethyl, cyclopropyl,or benzene, more preferably methyl.

In the present invention, R¹⁸ is preferably fluorine, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl,cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, oxo, nitrile, ahydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, methylsulfonyl,pyridine, or dimethylamino.

In the present invention, m is preferably an integer of 1 to 2, morepreferably 1.

In the present invention, n is preferably an integer of 0 to 1, morepreferably 1.

In the present invention, p is preferably 0.

In the present invention, q is preferably 0.

In the present invention, r is preferably an integer of 0 to 4, morepreferably an integer of 0 to 2.

In the present invention, s is preferably an integer of 0 to 2, morepreferably 1 or 2.

In the present invention, t is preferably an integer of 0 to 2.

In the present invention, X^(3a) is preferably an oxygen atom.

In the present invention, na is preferably an integer of 0 to 1.

In the present invention, qa is preferably 0.

In the present invention, ra is preferably an integer of 0 to 2.

In the present invention, preferred as the compound of general formula(I) is a combination of the preferred definitions of the ring, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁸⁻¹, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, L¹, L², L³, X¹, X², X³, X^(3a), m, n, na, p, q,qa, r, ra, s, and t.

In the present invention, the compound represented by general formula(I) is preferably a compound represented by the following generalformula (I-a), a salt, an N-oxide, or a solvate thereof, or a prodrug ofthese.

In the general formula (I-a), all symbols are as defined for the symbolsin [1] and [2] above.

More preferably, the compound represented by general formula (I) is acompound represented by the following general formula (I-1), a salt, anN-oxide, or a solvate thereof, or a prodrug of these.

In the general formula (I-1), all symbols are as defined for the symbolsin [1] and [2] above.

In the present invention, a more preferred aspect of the compoundrepresented by general formula (I) is a compound represented by thefollowing general formula (I-b), a salt, an N-oxide, or a solvatethereof, or a prodrug of these.

In the general formula (I-b), all symbols are as defined for the symbolsin [1] and [2] above.

An even more preferred aspect of the compound represented by generalformula (I) is a compound represented by the following general formula(I-c), a salt, an N-oxide, or a solvate thereof, or a prodrug of these.

In the general formula (I-c), all symbols are as defined for the symbolsin [1] and [2] above.

Preferred is a compound represented by the following general formula(I-d), a salt, an N-oxide, or a solvate thereof, or a prodrug of these.

In the general formula (I-d), all symbols are as defined for the symbolsin [1] and [2] above.

Further preferred is a compound represented by the following generalformula (I-e), a salt, an N-oxide, or a solvate thereof, or a prodrug ofthese.

In the general formula (I-e), all symbols are as defined for the symbolsin [1] and [2] above.

Particularly preferred is a compound represented by the followinggeneral formula (I-2), a salt, an N-oxide, or a solvate thereof, or aprodrug of these.

In the general formula (I-2), all symbols are as defined for the symbolsin [1], [2], and [5] above.

Most preferred is a compound represented by the following generalformula (I-4), a salt, an N-oxide, or a solvate thereof, or a prodrug ofthese.

In the general formula (I-4), all symbols are as defined for the symbolsin [1], [2], and [5] above.

In the present invention, a further preferred aspect of the compoundrepresented by general formula (I) is a compound represented by thefollowing general formula (I-f), a salt, an N-oxide, or a solvatethereof, or a prodrug of these.

In the general formula (I-f), all symbols are as defined for the symbolsin [1], [2], and [9] above.

Further preferred is a compound represented by the following generalformula (I-g), a salt, an N-oxide, or a solvate thereof, or a prodrug ofthese.

In the general formula (I-g), all symbols are as defined for the symbolsin [1], [2], and [9] above.

Preferred is a compound represented by the following general formula(I-h), a salt, an N-oxide, or a solvate thereof, or a prodrug of these.

In the general formula (I-h), all symbols are as defined for the symbolsin [1], [2], and [9] above.

Further preferred is a compound represented by the following generalformula (I-i), a salt, an N-oxide, or a solvate thereof, or a prodrug ofthese.

In the general formula (I-i), all symbols are as defined for the symbolsin [1], [2], and [9] above.

Particularly preferred is a compound represented by the followinggeneral formula (I-3), a salt, an N-oxide, or a solvate thereof, or aprodrug of these.

In the general formula (I-3), all symbols are as defined for the symbolsin [1], [2], and [9] above.

Most preferred is a compound represented by the following generalformula (I-5), a salt, an N-oxide, or a solvate thereof, or a prodrug ofthese.

In the general formula (I-5), all symbols are as defined for the symbolsin [1], [2], and [9] above.

In the present invention, L¹ is independently preferably propylene, andL² is independently preferably —CH═CH—, —NHCO—, —CONH—, —NHSO₂—, or—SO₂NH— in a group of general formulae selected from the generalformulae (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i),and (I-1). More preferably, L is propylene, and L² is —NHCO—, or —CONH—.Further preferably, L¹ is propylene, and L² is —NHCO—.

In the present invention, L¹ is independently preferably propylene in agroup of general formulae selected from the general formulae (I-2),(I-3), (I-4), and (I-5).

In the present invention, the most preferred aspect of the generalformula (I) includes the present compound of Example 1, the presentcompounds of Examples 2-1 to 2-47, the present compound of Example 3,the present compounds of Examples 4-1 to 4-3, the present compounds ofExamples 5 to 6, the present compounds of Examples 7-1 to 7-28, thepresent compounds of Examples 8 to 9, the present compounds of Examples10-1 to 10-12, the present compound of Example 11, the present compoundsof Examples 12-1 to 12-3, the present compounds of Examples 13 to 17,the present compounds of Examples 18-1 to 18-3, the present compound ofExample 19, the present compounds of Examples 20-1 to 20-5, the presentcompounds of Examples 21 to 22, the present compounds of Examples 23-1to 23-2, the present compounds of Examples 24 to 27, the presentcompounds of Examples 28-1 to 28-2, the present compounds of Examples 29to 30, the present compounds of Examples 31-1 to 31-2, the presentcompound of Example 32, the present compounds of Examples 33-1 to 33-5,the present compounds of Examples 34 to 36, the present compounds ofExamples 37-1 to 37-2, the present compounds of Examples 38-1 to 38-2,the present compound of Example 39, a salt, an N-oxide, or a solvatethereof, or a prodrug of these.

It is to be understood that all isomeric forms of the compounds fallwithin the scope of the present invention, unless otherwise specificallystated. For example, the alkyl, alkoxy, and alkylene include linear andbranched alkyl, alkoxy, and alkylene. The present invention alsoincludes all of the following: isomers due to a double bond, a ring, anda fused ring (E, Z, cis, and trans isomers), isomers due to the presenceof an asymmetric carbon (R and S isomers, α and β isomers, enantiomers,diastereomers), optical isomers involving optical rotation (D, L, d, lisomers), polar compounds separated by chromatography (high-polarity,and low-polarity compounds), equilibrium compounds, rotational isomers,mixtures of any proportions of these compounds, and racemic mixtures.The present invention also includes all isomers due to tautomerism.

As is clear for a skilled person, the following symbols as used hereinhave the following meaning, unless otherwise specifically stated.

represents a bond into the plane of the paper (i.e., the aconfiguration).

represents a bond out of the plane of the paper (i.e., the jconfiguration).

represents a mix of α and β configurations.

Salts

The compound represented by general formula (I) is converted into a saltusing a known method.

The salt is preferably a pharmaceutically acceptable salt.

Preferably, the salt is water soluble.

Examples of the pharmaceutically acceptable salt include acid additionsalts, alkali metal salts, alkali-earth metal salts, ammonium salts, andamine salts.

The acid addition salts may be inorganic acid salts, for example, suchas hydrochloride, hydrobromate, hydroiodide, sulfates, phosphates, andnitrates, or organic acid salts, for example, such as acetates,lactates, tartrates, benzoates, citrates, methanesulfonate,ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate,isethionates, glucuronates, and gluconates.

Examples of the alkali metal salts include potassium, and sodium.

Examples of the alkali-earth metal salts include calcium, and magnesium.

Examples of the ammonium salts include tetramethylammonium.

Examples of the amine salts include triethylamine, methylamine,dimethylamine, cyclopentylamine, benzylamine, phenethylamine,piperidine, monoethanolamine, diethanolamine,tris(hydroxymethyl)aminomethane, lysine, arginine, andN-methyl-D-glucamine.

The present compound may be transformed into an N-oxide using anymethod. As used herein, N-oxide refers to compounds of general formula(I) with oxidized nitrogen atoms.

The compound represented by general formula (I), and a salt thereof maybe transformed into a solvate.

Preferably, the solvate is non-toxic, and water soluble. Examples ofsuitable solvates include solvates using water, and solvates usingalcoholic solvents (for example, ethanol).

Prodrug

As used herein, a prodrug of the compound represented by general formula(I) refers to a compound that is transformed into the compound ofgeneral formula (I) in the body through reaction with, for example, anenzyme, and stomach acid. The following are examples of prodrugs of thecompounds represented by general formula (I): A compound of generalformula (I) with an amino group that is acylated, alkylated, orphosphorylated (for example, a compound of general formula (I) with anamino group that is eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, or tert-butylated); a compound of general formula (I)with a hydroxyl group that is acylated, alkylated, phosphorylated, orborated (for example, a compound of general formula (I) with a hydroxylgroup that is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated, ordimethylaminomethylcarbonylated; and a compound of general formula (I)with a carboxy group that is esterificated or amidated (for example, acompound of general formula (I) with a carboxy group that isethylesterificated, phenylesterificated, carboxymethylesterificated,dimethylaminomethylesterificated, pivaloyloxymethylesterificated,1-{(ethoxycarbonyl)oxy}ethylesterificated, phthalidylesterificated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterificated,1-{[(cyclohexyloxy)carbonyl]oxy}ethylesterificated, or methylamidated).These compounds may be produced by a method known per se. The prodrug ofthe compounds represented by general formula (I) may be a hydrate or anonhydrate. The prodrug of the compounds represented by general formula(I) may be one that transforms into the compound of general formula (I)under physiological conditions, such as described in Development ofDrugs, Vol. 7, Molecular Design, pp. 163-198, 1990, Hirokawa PublishingCompany.

The atoms constituting the compounds represented by general formula (I)may be replaced with their isotopes (for example, ²H, ³H, ¹³C, C, ¹⁵N,¹⁶N, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁷⁷Br, and ¹²⁵I)

Method of Production of Present Compounds

The present compounds represented by general formula (I) may be producedby known methods, for example, by the methods described below, methodsequivalent thereto, or the methods described in the Examples below. Inthe methods of production below, the feed compound may be in the form ofa salt. The salt may be any of the pharmaceutically acceptable saltsexemplified for the present compounds of general formula (I).

The present compound of general formula (I) of which L² is —NHCO—(general formula (IVa)), and the present compound of general formula (I)of which L² is —CONH— (general formula (IVb)) can be produced by themethods represented by the following reaction schemes (Ia) and (Ib),respectively.

In the formula, all symbols are as defined in [1] above.

In the formula, all symbols are as defined in [1] above.

Specifically, the present compound represented by general formula (IVa)can be produced by amidation reaction of the compound of general formula(IIa), and the compound of general formula (IIIa). The present compoundof general formula (IVb) can be produced by amidation reaction of thecompound of general formula (IIb), and the compound of general formula(IIIb).

The amidation reaction is known, and may be, for example,

(1) a method using an acid halide,(2) a method using a mixed acid anhydride, or(3) a method using a condensing agent.

The following describes these methods in detail.

(1) In the method using an acid halide, for example, carboxylic acid isreacted with an acid halide reagent (e.g., oxalyl chloride, or thionylchloride) at about −20° C. to reflux temperature in an organic solvent(e.g., chloroform, dichloromethane, diethyl ether, or tetrahydrofuran),or without solvent. The resulting acid halide is then reacted with anamine in an organic solvent (e.g., chloroform, dichloromethane, diethylether, or tetrahydrofuran) at about 0 to 40° C. in the presence of abase (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, or diisopropylethylamine). Alternatively, theacid halide may be reacted with an amine at about 0 to 40° C. in anorganic solvent (e.g., dioxane, or tetrahydrofuran), using an alkalineaqueous solution (e.g., sodium bicarbonate water, or a sodium hydroxidesolution).

(2) In the method using a mixed acid anhydride, for example, carboxylicacid is reacted with an acid halide (e.g., pivaloyl chloride, tosylchloride, or methyl chloride), or with an acid derivative (e.g., ethylchloroformate, or isobutyl chloroformate) at about 0 to 40° C. in anorganic solvent (e.g., chloroform, dichloromethane, diethyl ether, ortetrahydrofuran) or without solvent, in the presence of a base (e.g.,pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, ordiisopropylethylamine). The resulting mixed acid anhydride is thenreacted with an amine at about 0 to 40° C. in an organic solvent (e.g.,chloroform, dichloromethane, diethyl ether, or tetrahydrofuran).

(3) In the method using a condensing agent, for example, carboxylic acidis reacted with an amine at about 0° C. to reflux temperature in anorganic solvent (e.g., chloroform, dichloromethane, dimethylformamide,dimethylacetoamide, diethyl ether, or tetrahydrofuran) or withoutsolvent in the presence or absence of a base (e.g., pyridine,triethylamine, dimethylaniline, or dimethylaminopyridine), using acondensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridiniumiodine, or1-propanephosphonic acid cyclic anhydride (T3P)), with or without1-hydroxybenzotriazole (HOBt).

Desirably, the reactions (1), (2), and (3) are performed under anhydrousconditions in an inert gas (e.g., argon, or nitrogen) atmosphere.

The present compound of general formula (I) of which L² is —NHSO₂—(general formula (IVc)), and the present compound of general formula (I)of which L² is —SO₂NH— (general formula (IVd)) can be produced by themethods represented by the following reaction schemes (Ic) and (Id),respectively.

In the formula, all symbols are as defined in [1] above.

In the formula, all symbols are as defined in [1] above.

Specifically, the present compound represented by general formula (IVc)can be produced by Sulfonamidation reaction of the compound of generalformula (IIc), and the compound of general formula (IIIc). The presentcompound of general formula (IVd) can be produced by Sulfonamidationreaction of the compound of general formula (IId), and the compound ofgeneral formula (IIId).

The Sulfonamidation reaction is known. For example, sulfonic acid isreacted with an acid halide (e.g., oxalyl chloride, thionyl chloride,phosphorous pentachloride, or phosphorous trichloride) at −20° C. toreflux temperature in an organic solvent (e.g., chloroform,dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, ormethyl t-butyl ether) or without solvent. The resulting sulfonyl halideis then reacted with an amine at about 0 to 40° C. in an organic solvent(e.g., chloroform, dichloromethane, dichloroethane, diethyl ether, ortetrahydrofuran) in the presence of a base (e.g., diisopropylethylamine,pyridine, triethylamine, dimethylaniline, or dimethylaminopyridine).

The present compound of general formula (I) of which L² is —NHCH₂—(general formula (IVe)), and the present compound of general formula (I)of which L² is —CH₂NH— (general formula (IVf)) can be produced by themethods represented by the following reaction schemes (Ie) and (If),respectively.

In the formula, all symbols are as defined in [1] above.

In the formula, all symbols are as defined in [1] above.

Specifically, the present compound represented by general formula (IVe)can be produced by reductive amination reaction of the compound ofgeneral formula (IIe), and the compound of general formula (IIIe). Thepresent compound of general formula (IVf) can be produced by reductiveamination reaction of the compound of general formula (IIf), and thecompound of general formula (IIIf).

The reductive amination reaction is known. For example, the reaction isperformed in an organic solvent (e.g., dichloroethane, dichloromethane,dimethylformamide, acetic acid, or a mixture of these) at about 0 to 40°C. in the presence of a reducing agent (e.g., sodiumtriacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride).

The present compound of general formula (I) of which L² is —OCH₂—(general formula (IVg)), and the present compound of general formula (I)of which L² is —CH₂O— (general formula (IVh)) can be produced by themethods represented by the following reaction schemes (Ig) and (Ih),respectively.

In the formula, Xg represents halogen, tosylate, or mesylate, and theother symbols are as defined in [1] above.

In the formula, Xh represents halogen, tosylate, or mesylate, and theother symbols are as defined in [1] above.

Specifically, the present compound represented by general formula (IVg)can be produced by etherification reaction of the compound of generalformula (IIg), and the compound of general formula (IIIg). The presentcompound of general formula (IVh) can be produced by etherificationreaction of the compound of general formula (IIh), and the compound ofgeneral formula (IIIh).

The etherification reaction is known. For example, the reaction isperformed in an organic solvent (e.g., dimethylformamide,dimethylsulfoxide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, or methyl t-butyl ether) at about 0 to 100° C. in thepresence of an alkali metal hydroxide (e.g., sodium hydroxide, potassiumhydroxide, or lithium hydroxide), an alkali earth metal hydroxide (e.g.,barium hydroxide, or calcium hydroxide), a carbonate (e.g., sodiumcarbonate, or potassium carbonate), or an aqueous solution or a mixtureof these.

The present compound of general formula (I) of which L² is —SCH₂—(general formula (IVj)), and the present compound of general formula (I)of which L² is —CH₂S— (general formula (IVk)) can be produced by themethods represented by the following reaction schemes (Ij) and (Ik),respectively.

In the formula, Xj represents halogen, tosylate, or mesylate, and theother symbols are as defined in [1] above.

In the formula, Xk represents halogen, tosylate, or mesylate, and theother symbols are as defined in [1] above.

Specifically, the present compound represented by general formula (IVj)can be produced by thioetherification reaction of the compound ofgeneral formula (IIj), and the compound of general formula (IIIj). Thepresent compound of general formula (IVk) can be produced bythioetherification reaction of the compound of general formula (IIk),and the compound of general formula (IIIk)

The thioetherification reaction is known. For example, the reaction isperformed in an organic solvent (e.g., dimethylformamide,dimethylsulfoxide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, or methyl t-butyl ether) at about 0 to 100° C. in thepresence of an alkali metal hydroxide (e.g., sodium hydroxide, potassiumhydroxide, or lithium hydroxide), an alkali earth metal hydroxide (e.g.,barium hydroxide, or calcium hydroxide), a carbonate (e.g., sodiumcarbonate, or potassium carbonate), or an aqueous solution or a mixtureof these.

The present compound of general formula (I) of which L² is —S(O)CH₂— or—SO₂CH₂— can be produced by appropriately subjecting the sulfur atom ofthe present compound of the general formula (IVj) above to oxidationreaction.

The present compound of general formula (I) of which L² is —CH₂S(O)— or—CH₂SO₂— can be produced by appropriately subjecting the sulfur atom ofthe present compound of the general formula (IVk) above to oxidationreaction.

The oxidation reaction (sulfoxidation reaction: —SCH₂—→—S(O)CH₂—, or—CH₂S—→—CH₂S(O)—) is known. For example, the reaction is performed in anorganic solvent (e.g., dichloromethane, chloroform, benzene, hexane,methanol, t-butyl alcohol, acetone, acetonitrile, tetrahydrofuran,acetic acid, or N,N-dimethylformamide), or in water or in a mixedsolvent of these at about −40 to 0° C. in the presence of 1 to 1.2equivalents of an oxidizing agent (e.g., hydrogen peroxide, sodiumperiodate, acyl nitrite, sodium perborate, sodium hypochlorite, aperacid (e.g., 3-chloroperbenzoic acid, or peracetic acid), an Oxone®(potassium peroxymonosulfate; hereinafter, simply referred to as Oxone),potassium permanganate, chromic acid, or dimethyldioxolan).

The oxidation reaction (sulfonation reaction: —SCH₂— →—SO₂CH₂—, or—CH₂S—→—CH₂SO₂—) is known. For example, the reaction is performed in asuitable organic solvent (e.g., dichloromethane, chloroform, benzene,hexane, methanol, t-butyl alcohol, acetone, acetonitrile,tetrahydrofuran, acetic acid, or N,N-dimethylformamide), or in water orin a mixed solvent of these at about 20 to 60° C. in the presence of anexcess oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acylnitrite, sodium perborate, sodium hypochlorite, a peracid (e.g.,3-chloroperbenzoic acid, or peracetic acid), Oxone® (potassiumperoxymonosulfate), potassium permanganate, chromic acid, ordimethyldioxolan).

The present compound of general formula (I) of which L² is —CH═CH—(general formula (IVm)) can be produced by the method represented by thefollowing reaction scheme (Im).

In the formula, all symbols are as defined in [1] above.

Specifically, the present compound represented by general formula (IVm)can be produced by the Heck reaction of the compound of general formula(IIm) with the compound of general formula (Vm) produced by vinylationreaction of the compound represented by general formula (IIIm).

The vinylation reaction is known. For example, the reaction is performedusing the compound of general formula (IIIm), andmethyltriphenylphosphonium bromide in an organic solvent (e.g.,acetonitrile, methylene chloride, tetrahydrofuran, toluene, benzene, oran appropriate mixed solvent of these organic solvents) at about 0° C.to 120° C. in the presence of a base (for example, potassium carbonate,sodium hydride, potassium hydride, n-butyllithium, potassiumtert-butoxide, or 1,8-diazabicyclo[5.4.0]undec-7-ene triethylamine(DBU)).

The Heck reaction is known. For example, the reaction is performed in anorganic solvent (for example, toluene, diethyl ether, benzene,dichlorobenzene, dimethylformamide, or an appropriate mixed solvent ofthese organic solvents) at about 0° C. to 120° C. in the presence of abase (for example, tripotassium phosphate, sodium bicarbonate, ortriethylamine), and a catalyst (for example, a palladium catalyst, forexample, such as palladium chloride, palladium acetate, andtetrakis(triphenylphosphine)palladium(0); a nickel catalyst, forexample, such as tetrakis(triphenylphosphine)nickel, andbis(triphenylphosphine)nickel(II); a cobalt catalyst, for example, suchas cobalt chloride; a copper catalyst, for example, such as copperchloride; a zinc catalyst, for example, such as zinc; or an appropriatemixed catalyst of these catalysts), with or without a phosphorus reagent(for example, 1,3-bis(diphenylphosphino)propane (dppp), orPh₂P—(CH₂)₆—PPh₂).

The present compound of general formula (I) of which L² is —CH₂CH₂— canbe produced by appropriately subjecting the —CH═CH— of the presentcompound of the general formula (IVm) above to reduction reaction.

The reduction reaction is known. For example, the reaction is performedin an organic solvent (for example, tetrahydrofuran, dioxane,dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene,acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water,ethyl acetate, acetic acid, or an appropriate mixed solvent of theseorganic solvents) in a hydrogen atmosphere under ordinary pressure orincreased pressure, in the presence of ammonium formate or in thepresence of hydrazine at about 0 to 200° C., in the presence of ahydrogenation catalyst (e.g., palladium-carbon, palladium black,palladium, palladium hydroxide, platinum dioxide, platinum-carbon,nickel, Raney nickel, or ruthenium chloride), with or without an acid(e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid,tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid,trifluoroacetic acid, or formic acid)

The compound of general formula (IIIa) in reaction scheme (Ia) of whichq is 0, and m is 1 (general formula (IIIaa)) can be produced by themethod represented by the following reaction scheme (Iaa).

In the formula, Raa is C1-4 alkyl, and the other symbols are as definedin [1] and [2] above.

Specifically, the compound represented by general formula (IIIaa) can beproduced by subjecting the compound of general formula (VIaa) producedby vinylation reaction of the compound of general formula (Vaa) tocyclization reaction, and to hydrolysis reaction.

The vinylation reaction is known. For example, the reaction is performedusing the compound of general formula (Vaa), andmethyltriphenylphosphonium bromide in an organic solvent (for example,acetonitrile, methylene chloride, tetrahydrofuran, toluene, benzene, oran appropriate mixed solvent of these organic solvents) at about 0° C.to 120° C. in the presence of a base (for example, potassium carbonate,sodium hydride, potassium hydride, n-butyllithium, potassiumtert-butoxide, or 1,8-diazabicyclo[5.4.0]undec-7-ene triethylamine(DBU)).

The cyclization reaction is known. For example, the reaction isperformed using the compound of general formula (VIaa), and adiazocompound in an organic solvent (for example, toluene, benzene, methylenechloride, dichloroethane, methanol, ethanol, hexane, tetrahydrofuran,water, or an appropriate mixed solvent of these organic solvents) atabout −78° C. to 120° C. in the presence of a catalyst (e.g., aruthenium catalyst, for example, such as a dichloro(cymene)rutheniumdimer ([Ru(p-cymene)Cl₂]₂), RuCl₂(PPh₃)₃, and RuCl(Cp)(PPh₃)₂; a rhodiumcatalyst, for example, such as Rh₂(O—CO-heptyl)₄, Rh₂(O—CO-tBu)₄,Rh₂(OAc)₄, Rh₂(O-Piv)₄, Rh₂((S)-PTTL)₄, Rh₂((S)-DOSP)₄, Rh₂(esp)₂, andRh₂((S)-NTTL)₄; a silver catalyst, for example, such as silver(I)tetrafluoroborate; a copper catalyst, for example, such as CuOTf,Cu(OAc)₂, and [Cu(MeCN)₄]PF₆; a tin catalyst, for example, such asSn(tpp)(OTf)₂; an iron catalyst, for example, such as [Fe(Cp)(CO)₂(thf)]BF₄; a cobalt catalyst,2,6-bis(4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine,2,6-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine, or2,6-bis((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine). In thecyclization reaction, an optically active tricyclic spiro compound (anoptical isomer of the compound represented by general formula (VIIaa))can be produced by using a known optically active asymmetric catalyst.

The hydrolysis reaction (deprotection reaction of the carboxyl group) isknown. Alkali hydrolysis is an example of the hydrolysis reaction. Forexample, the deprotection reaction by alkali hydrolysis is performed inan organic solvent (e.g., methanol, tetrahydrofuran, or dioxane) at atemperature of 0 to 100° C. using an alkali metal hydroxide (e.g.,sodium hydroxide, potassium hydroxide, or lithium hydroxide), an alkaliearth metal hydroxide (e.g., barium hydroxide, or calcium hydroxide), acarbonate (e.g., sodium carbonate, or potassium carbonate), or anaqueous solution or a mixture of these.

The compound of general formula (IIIb) in reaction scheme (Ib), thecompound of general formula (IIId) in reaction scheme (Id), or thecompound of general formula (IIIf) in reaction scheme (If) of which m is1 can be produced from the compound of general formula (IIIaa) inreaction scheme (Iaa) using a known method, for example, such asdescribed in Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc., 1999).

The compound of general formula (IIIc) in reaction scheme (Ic) of whichm of an integer of 1 can be produced from the compound of generalformula (IIIaa) in reaction scheme (Iaa) using a known method, forexample, such as described in Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2nd Edition (Richard C. Larock,John Wiley & Sons Inc., 1999).

The compound of general formula (IIIe) in reaction scheme (Ie), or thecompound of general formula (IIIm) in reaction scheme (Im) of which m is1 can be produced from the compound of general formula (IIIaa) inreaction scheme (Iaa) using a known method, for example, such asdescribed in Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc., 1999).

The compound of general formula (IIIg) in reaction scheme (Ig), or thecompound of general formula (IIIj) in reaction scheme (Ij) of which m is1 can be produced from the compound of general formula (IIIaa) inreaction scheme (Iaa) by reducing the carboxylic acid to produce aprimary alcohol derivative, and transforming the alcohol derivative intoa halogen derivative, a tosylate derivative, or a mesylate derivative,using a known method, for example, such as described in ComprehensiveOrganic Transformations: A Guide to Functional Group Preparations, 2ndEdition (Richard C. Larock, John Wiley & Sons Inc., 1999).

The compound of general formula (IIIh) in reaction scheme (Ih) of whichm is 1 can be produced from the compound of general formula (IIIaa) inreaction scheme (Iaa) using a known method, for example, such asdescribed in Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc., 1999), or in Tetrahedron Letter, Vol. 28, pp.4489-4492, 1987.

The compound of general formula (IIIk) in reaction scheme (Ik) of whichm is 1 can be produced by producing a secondary alcohol derivative fromthe compound of general formula (IIIaa) in reaction scheme (Iaa), andtransforming the alcohol derivative into a thiol derivative, using aknown method, for example, such as described in Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, 2nd Edition(Richard C. Larock, John Wiley & Sons Inc., 1999), or in TetrahedronLetter, Vol. 28, pp. 4489-4492, 1987.

In the compounds of general formulae (IIIa), (IIIb), (IIIc), (IIId),(IIIe), (IIIf), (IIIg), (IIIh), (IIIj), (IIIk), and (IIIm) used asstarting materials in the reaction schemes, the compounds with an m of1, and a q of 1 to 3, or the compounds with an m of 2 to 4, and a q of 1to 6 are known, or can be produced with ease using a known method, forexample, such as described in Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2nd Edition (Richard C. Larock,John Wiley & Sons Inc., 1999).

The compounds of general formulae (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIj), (IIk), (IIm), and (Vaa) used as startingmaterials in the reaction schemes are known, or can be produced withease using a known method, for example, such as described inComprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc.,1999).

The present compound having an amino group, a carboxyl group, or ahydroxyl group can be produced using a compound that has been protected,as required, by a protecting group commonly used for such groups, forexample, such as described in Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2nd Edition (Richard C. Larock,John Wiley & Sons Inc., 1999). The present compound can be obtained byperforming a known deprotection reaction, for example, the deprotectionreaction described in Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc., 1999) after the completion of the amidation reactionof reaction scheme (Ia) or (Ib), the Sulfonamidation reaction ofreaction scheme (Ic) or (Id), the reductive amination reaction ofreaction scheme (Ie) or (If), the etherification reaction of reactionscheme (Ig) or (Ih), the thioetherification reaction of reaction scheme(Ij) or (Ik), or the Heck reaction of reaction scheme (Im), or after asuitable reaction process.

The present compounds of general formula (I) other than the compoundsdescribed above may be produced by combining the methods described inthe Examples described in this specification, or by combining knownmethods, for example, such as described in Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, 2nd Edition(Richard C. Larock, John Wiley & Sons Inc., 1999).

When the present compound is an optically active compound, the compoundalso can be produced using a starting material or a reagent havingoptical activity, or by optically separating a racemic intermediate andderiving the present compound therefrom, or optically separating aracemic form of the present compound.

The optical separation method is known. For example, a salt or a complexis formed with other optically active compound, and the compound ofinterest is isolated after recrystallization, or the compound isdirectly separated using, for example, a chiral column.

In the reactions used herein, reactions involving heat may be performedusing a water bath, an oil bath, a sand bath, or a microwave, as isevident to a skilled person.

In the reactions used herein, a reagent may be used that is supported ona solid-phase polymer (for example, polystyrene, polyacrylamide,polypropylene, or polyethylene glycol), as appropriate.

In the reactions used herein, the reaction product may be purified byusing ordinary purification means, for example, such as distillationunder ordinary pressure or reduced pressure, high-performance liquidchromatography using silica gel or magnesium silicate, thin-layerchromatography, methods using an ion-exchange resin or a scavengerresin, column chromatography, washing, and recrystallization. Thepurification may be performed after each reaction, or after severalreactions.

Toxicity

The present compound has low toxicity, and is safe to use as a drug.

Drug Applications

The present invention is intended to create compounds having a strongantagonistic activity against the EP₄ receptor, and that show desirablepharmacokinetics, and to find a compound that is useful as a preventiveand/or a therapeutic drug against diseases caused by EP₄ receptoractivation.

The present compound shows antagonistic activity against the EP₄receptor, and is useful as a preventive and/or a therapeutic agentagainst diseases caused by EP₄ receptor activation, for example, such asa bone disease, a cancer, a systemic granulomatous disease, an immunedisease, an allergic disease, asthma, alveolar pyorrhea, gingivitis,periodontitis, Alzheimer's, Kawasaki disease, burn, multiple organfailure, chronic headache, pain, vasculitis, venous incompetence,varicose veins, aneurysm, aortic aneurysm, anal fistula, diabetesinsipidus, stress, endometriosis, uterine adenomyosis, patent ductusarteriosus in neonates, and cholelithiasis.

Specific examples of the bone disease include osteoporosis, rheumatoidarthritis, osteoarthritis, and skeletal dysplasias. Examples of thecancer include breast cancer, ovarian cancer, colorectal cancer (forexample, colon cancer), lung cancer (for example, non-small cellcancer), prostate cancer, head and neck cancer (for example, oralsquamous cell carcinoma, head and neck squamous cell carcinoma,pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer,acoustic neuroma), lymphoma (for example, B cell lymphoma, T celllymphoma), uveal melanoma, thymoma, mesothelioma, esophageal cancer,stomach cancer, duodenal cancer, hepatocellular carcinoma,cholangiocarcinoma, gallbladder cancer, pancreatic cancer, renal cellcarcinoma, renal pelvis and ureter cancer, bladder cancer, penilecancer, testicular cancer, uterus cancer, vaginal cancer, vulvar cancer,skin cancer (for example, malignant melanoma), malignant bone tumor,soft tissue sarcoma, chondrosarcoma, leukemia (for example, acutemyelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenousleukemia, chronic lymphocytic leukemia), myelodysplastic syndrome, andmultiple myeloma. Examples of the immune disease include amyotrophiclateral sclerosis (ALS), multiple sclerosis, Sjogren's syndrome,systemic lupus erythematosus, and AIDS. Examples of the allergic diseaseinclude allergic conjunctivitis, allergic rhinitis, contact dermatitis,and psoriasis. Examples of the chronic headache include migraine,tension headache, a combination of these, and cluster headache.

The present compound may be administered as a concomitant drug withother medicinal agent to:

1) complement and/or enhance the preventive and/or therapeutic effect ofthe compound,

2) improve the kinetics and absorption of the compound, and reduce thedose of the compound, and/or

3) reduce the side effects of the compound.

The concomitant drug using the present compound with other medicinalagent may be administered in the form of a compounding agent containingthe both components in the same preparation, or in the form of separatepreparations. When administered as separate preparations, thepreparations may be administered at the same or different times. Whenadministered at different times, the present compound may beadministered before other medicinal agent, or other medicinal agent maybe administered before the present compound. These may be administeredusing the same or different method.

The disease for which the concomitant drug shows a preventive and/ortherapeutic effect is not particularly limited, provided that thedisease is one in which the preventive and/or therapeutic effect of thepresent compound is complemented and/or enhanced.

Examples of medicinal agents that complement and/or enhance thepreventive and/or therapeutic effect of the present compound in aorticaneurysm include HMG-CoA reductase inhibitors, antihypertensives, andtetracycline antibiotics.

Examples of the HMG-CoA reductase inhibitors include pravastatin(sodium), simvastatin, fluvastatin (sodium), cerivastatin (sodium),itavastatin, atorvastatin (calcium hydrate), lovastatin, andpitavastatin (calcium).

Examples of the antihypertensives include calcium antagonists,angiotensin II antagonists, angiotensin converting enzyme inhibitors,phosphodiesterase 4 inhibitors, diuretics, prostaglandins, aldosteroneantagonists, and sympathetic blocking agents.

Examples of the calcium antagonists include nifedipine, benidipinehydrochloride, diltiazem hydrochloride, verapamil hydrochloride,nisoldipine, nitrendipine, bepridil hydrochloride, amlodipine besilate,lomerizine hydrochloride, and efonidipine hydrochloride.

Examples of the angiotensin II antagonists include losartan (potassium),candesartan (cilexetil), valsartan, irbesartan, olmesartan (medoxomil),and telmisartan.

Examples of the angiotensin converting enzyme inhibitors includealacepril, imidapril hydrochloride, quinapril hydrochloride, temocaprilhydrochloride, delapril hydrochloride, benazepril hydrochloride,captopril, trandolapril, perindopril erbumine, enalapril maleate, andlisinopril.

Examples of the phosphodiesterase 4 inhibitors include cilomilast,roflumilast, arofylline, atizoram, cipamfylline, and rolipram.

Examples of the diuretics include acetazolamide, aminophylline,isosorbide, dichlorphenamide, spironolactone, trichlormethiazide,furosemide, mannitol, methazolamide, and mefruside.

Examples of the aldosterone antagonists include drospirenone,metyrapone, potassium canrenoate, canrenone, and eplerenone.

Examples of the tetracycline antibiotics include doxycycline.

Examples of the medicinal agents that complement and/or enhance thepreventive and/or therapeutic effect of the present compound in cancerinclude alkylating agents, antimetabolites, anti-cancer antibiotics,plant-based preparations, hormonal agents, platinum compounds,topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies,anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies,proteasome inhibitors, HDAC inhibitors, and immunomodulators.

Examples of the alkylating agents include cyclophosphamide, ifosfamide,dacarbazine, temozolomide, nimustine hydrochloride, ranimustine,bendamustine, thiotepa, and carboquone.

Examples of the antimetabolites include methotrexate, pemetrexed,fluorouracil, tegafur, tegafur uracil, tegafur gimestat otastatpotassium, doxifluridine, capecitabine, cytarabine, gemcitabinehydrochloride, fludarabine, nelarabine, carmofur, and procarbazinehydrochloride.

Examples of the anti-cancer antibiotics include mitomycin C, doxorubicinhydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride,epirubicin, chromomycin A3, bleomycin, peplomycin sulfate, andtherarubicin.

Examples of the plant-based preparations include irinotecanhydrochloride, etoposide, vincristine sulfate, vinblastine sulfate,vindesine sulfate, vinorelbine tartrate, docetaxelhydrate, eribulinmesylate, and paclitaxel.

Examples of the hormonal agents include estramustine sodium phosphate,flutamide, bicalutamide, goserelin acetate, leuprorelin acetate,tamoxifen citrate, toremifene citrate, anastrozole, letrozole,exemestane, mepitiostane, medroxyprogesterone acetate, epitiostanol,fosfestrol, fadrozole hydrochloride hydrate, abiraterone, fulvestrant,and aminoglutethimide.

Examples of the platinum compounds include carboplatin, cisplatin,nedaplatin, and oxaliplatin.

Examples of the topoisomerase inhibitors include topotecan, andsobuzoxane.

Examples of the kinase inhibitors include EGFR inhibitors such aserlotinib, gefitinib, and afatinib; HER2 inhibitors such as lapatinib;BCR-ABL inhibitors such as imatinib; ALK inhibitors such as crizotinib;and multi-kinase inhibitors such as regorafenib, and dasatinib.

Examples of the anti-CD20 antibodies include rituximab, ibritumomab,ibritumomab tiuxetan, and ocrelizumab.

Examples of the anti-HER2 antibodies include trastuzumab, trastuzumabemtansine, and pertuzumab.

Examples of the anti-EGFR antibodies include cetuximab, and panitumumab.

Examples of the anti-VEGF antibodies include bevacizumab.

Examples of the proteasome inhibitors include bortezomib.

Examples of the HDAC inhibitors include vorinostat.

Examples of the immunomodulators include thalidomide, lenalidomide, andpomalidomide.

Examples of the medicinal agents that complement and/or enhance thepreventive and/or therapeutic effect of the present compound in paininclude N-type calcium channel inhibitors, nitrogen oxide synthetase(NOS) inhibitors, and cannabinoid-2 receptor stimulating reagents.

Examples of the N-type calcium channel inhibitors include cilnidipine.

Examples of the nitrogen oxide synthetase (NOS) inhibitors includeD-arginine, and NG-monomethyl-L-arginine.

The mass ratio of the present compound and other medicinal agent is notparticularly limited.

The medicinal agents may be administered in any combination of two ormore.

The medicinal agents that complement and/or enhance the preventiveand/or therapeutic effect of the present compound are not limited to thecompounds that are currently available with the mechanisms above, butinclude compounds that will be available in the future.

To use the present invention compounds as a single drug or a companiondrug with other drugs for the prevention and/or treatment of saiddiseases, preparations are usually formed in active substances andvarious additives or pharmaceutically acceptable excipients, and areadministered as oral or parenteral preparation systemically or locally.The pharmaceutically acceptable excipients mean materials except activesubstances which are generally used for preparations. Thepharmaceutically acceptable excipients are preferably excipients whichare harmlessness, and do not show any pharmacological effect and inhibittreatment effect of the active substances at the dosage of the drugproducts. In addition, the pharmaceutically acceptable excipients can beused to enhance effectiveness of the active substances, make productionof the drugs easy, stabilize quality and improve usability.Specifically, the material described in “Iyakuhintenkabutujiten”(yakujinippousha, 2000), (edited by nihonniyakuhinntennkazai kyokai)”,etc. may be selected according to intentions.

Dosage forms for administration includes, for example, oral preparation(e.g.: tablets, capsules, granules, powders, oral solutions, syrups,oral jelly agents, etc.), oro-mucosal preparation (e.g.: tablets fororo-mucosal application, sprays for oro-mucosal application, semi-solidpreparations for oro-mucosal application, gargles, etc.), preparationsfor injection (e.g.: injections, etc.), preparations for dialysis (e.g.:dialysis agents, etc.), preparation for inhalation (e.g.: inhalations,etc.), preparation for ophthalmic application (e.g.: ophthalmic liquidsand solutions, ophthalmic ointments, etc.), preparation for oticapplication (e.g.: ear preparation, etc.), preparations for nasalapplication (nasal preparations, etc.), preparation for recta (e.g.:suppositories, semi-solid preparations for rectal application, enemasfor rectal application, etc.), preparations for vaginal application(e.g.: tablets for vaginal use, suppositories for vaginal use, etc.) andpreparation for cutaneous application (e.g.: solid preparations forcutaneous application, liquids and solutions for cutaneous application,sprays, ointment, creams, gels, patches, etc.).

[Oral Preparation]

Oral preparation include, for example, tablets, capsules, granules,powders, liquids and solution for oral administration, syrups, Jelliesfor oral administration, etc. As oral preparation, there areImmediate-release dosage forms showing a release pattern of activesubstances that is not intentionally modified and modified-releasedosage forms are preparations showing modified pattern of activesubstances that is suitably modified for the desired purpose by means ofa specific formulation design and/or manufacturing methods.Modified-release dosage forms include enteric-coated andextended-release preparations. Enteric-coated (delayed-release)preparations release the bulk of the active substances not in stomachbut mainly in small intestine, in order to prevent degradation ordecomposition of the active substances in stomach or to decrease theirritation of the active substances on stomach. Enteric-coatedpreparations are generally coated with an acid-insoluble enteric film.Extended-release preparations are designed to control the release rateand release period of active substances and to restrict the release toappropriate sites in the gastrointestinal tracts in order to decreasethe dosing frequency and/or to reduce adverse or side effects.Extended-release preparations are generally prepared by using suitableagents that prolong the release of the active substances. Oral dosageforms such as capsules, granules and tablets can be coated withappropriate coating agents, such as sugars, sugar alcohols, or polymers,for the purpose of enabling the ingestion easy or of preventingdegradation of the active substances.

(1) Tablets

Tablets are solid preparation having a desired shape and size, intendedfor oral administration, and include orally disintegrating tablets,chewable tablets, effervescent tablets, dispersible tablets, solubletablets besides generally called tablets such as plain tablets,film-coated tablets, sugar-coated tablets, multi-layered tablets andpressure-coated tablets, etc. Plain tables are usually preparedaccording to the following methods (a), (b) and (c):

(a) Mix homogeneously active substances and excipients such as diluents,binders and disintegrators, granulate with water or a binder solution bysuitable methods, mix with a lubricant, and then compress into a desiredshape and size;(b) Mix homogeneously active substances and excipients such as diluents,binders,and disintegrators, and then directly compress, or compress after addingactive substances and lubricant to granules previously prepared fromexcipients and then mixing homogeneously;(c) Mix homogeneously active substances and excipients such as diluentsand binders, moisten with a solvent, form into a certain shape and size,and then dry by a suitable methods; Film-coated tablets can be prepared,usually, by coating plain tablets using suitable coating agents such aspolymers. Sugar-coated tablets can be prepared, usually, by coatingplain tablets using suitable coating agents including sugars and sugaralcohols. Multiple-layer tablets can be prepared by compressing granulesof different compositions to form layered tablets by a suitable method.Pressure-coated tablets can be prepared by compressing granules to coverinner core tablets with different compositions. In addition, tablets canbe prepared as enteric coated tablets or timed-release tablet bysuitable well-known methods. Orally disintegrating tablets, chewabletablets, effervescent tablets, dispersible tablets, soluble tablets aretablets which are added distinct role by selecting suitable excipients,and can be prepared according to said methods. Orally disintegratingtablets are tablets which are quickly dissolved or disintegrated in theoral cavity; Chewable tablets are tablets which are administered bychewing; Effervescent tablets are tablets which are quickly dissolved ordispersed with bubbles in water; Dispersible tablets are tablets whichare administered after having been dispersed in water; Soluble tabletsare tablets which are administered after having been dissolved in water.Effervescent tablets can be prepared using suitable acidic substancesand carbonates or hydrogen carbonates as excipients.

(2) Capsules

Capsules are preparations enclosed in capsules or wrapped with capsulebases, intended for oral administration. Capsules are classified intohard capsules and soft capsules. Hard capsules can be prepared by amethod where a homogeneous mixture of active substances with diluentsand other suitable excipients, or granules or formed masses prepared bya suitable methods, are filled into capsule shells as they are or afterslight compression. Soft capsules can be prepared by a method whereactive substances and suitable excipients are mixed, enclosed by asuitable capsule base such as gelation plasticized by addition ofglycerin, D-sorbitol, etc. and molded in a suitable shape and size.Capsules can be prepared as enteric-coated or extended-release capsulesby a suitable well-known method. Coloring agents and preservatives, etc.may be added to the capsule bases.

(3) Granules

Granules are preparations prepared by granulation, and includeeffervescent granules besides generally called granules. Granules can beprepared by the following methods (a), (b), and (c);

(a) To powdery active substances add diluents, binders, disintegrators,or other suitable excipients, mix to homogenize, and granulate by asuitable method;(b) To previously granulated active substances add excipients such asdiluents, and mix to homogenize;(c) To previously granulated active substances add excipients such asdiluents, and granulate by a suitable method; Granules can be coated ifnecessary, and can be prepared as enteric-coated or extended-releasegranules. Effervescent granules can be prepared using suitable acidicsubstances and carbonates or hydrogen carbonates. Effervescent granulesare granules which are quickly dissolved or dispersed with bubbles inwater. Granules can be prepared as fine grain agents by adjustingparticle size.

(4) Powders

Powders are preparations in powder form, and are usually prepared byhomogeneously mixing active substances with diluents or other suitableexcipients.

(5) Liquids and Solution for Oral Administration

Liquids and solution for oral administration are preparations in liquidform or flowable and viscous gelatinous state, and elixirs, suspensions,emulsions and lemonades are included in this category besides generallycalled Liquids and solution for oral administration. Liquids andsolution for oral administration are usually prepared by dissolving,emulsifying or suspending active substances in purified water togetherwith excipients, and by filtering if necessary. Elixirs are clear,sweetened and aromatic liquid preparations, containing ethanol, and areusually prepared by dissolving solid active substances or theirextractives in ethanol and purified water, adding aromatic agents andsucrose, other sugars or sweetening agents, and clarifying by filtrationor other procedure. Suspensions are liquid preparations of activesubstances suspended finely and homogeneously in a vehicle, and areusually prepared by adding suspending agent or other suitable excipientsand purified water or oil to solid active substances, and suspendinghomogeneously as the whole by a suitable method. Emulsions are liquidpreparations of active substances emulsified finely and homogeneously ina liquid vehicle, and are usually prepared by adding emulsifying agentsand purified water to liquid active substances, and emulsifying finelyand homogeneously by a suitable method. In addition, Lemonades are sweetand sour, clear liquid preparations, intended for oral administration.

(6) Syrups

Syrups are viscous liquid or solid preparations containing sugars orsweetening agents, and include preparation for syrups. Syrups areusually prepared by dissolving, mixing, suspending or emulsifying activesubstances in a solution of sucrose, other sugars or sweetening agents,or in simple syrup. Where necessary, the mixture is boiled, and filteredwhile hot. Preparations for syrups are preparations in form of granulesor powders, which becomes syrups by adding water. They may be termed“dry syrups”. Preparations for syrups are usually prepared with sugarsor sweetening agents according to said preparation method of granules orpowders.

(7) Jellies for Oral Administration

Jellies for oral administration are non-flowable gelatinous preparationshaving a certain shape and size, and usually prepared by mixing activesubstances with suitable excipients and polymer gel base, gelatinizingand forming into a certain shape and size by a suitable method.

[Preparation for Oro-Mucosal Application] (1) Tablets for Oro-MucosalApplication

Tablets for oro-mucosal application are solid preparations having acertain form, and include troches/lozenges, sublingual tablets, buccaltablets, mucoadhesive tablets and medicated chewing gums. Preparationsfor oro-mucosal application are usually prepared according to saidmethod of tablets. Troches/lozenges are tablets for oro-mucosalapplication, which are gradually dissolved or disintegrated in themouth; Sublingual tablets are tablets for oro-mucosal application, fromwhich active substances are quickly dissolved sublingually and absorbedvia the oral mucosa; Buccal tablets are tablets for oro-mucosalapplications, from which the active substances are dissolved graduallybetween the cheek and teeth, and absorbed via the oral mucosa;Mucoadhesive tablets are tablets for oro-mucosal application that areapplied by adhesion to the oral mucosa; Medicated chewing gums aretablets for oro-mucosal application, releasing active substances bychewing.

(2) Spray for Oro-Mucosal Application

Spray for oro-mucosal application are preparation that are appliedactive substances by spraying into the oral cavity in mist, powder, foamor paste forms, and are usually prepared by dissolving or suspendingactive substances and suitable excipients in a solvent, filter, wherenecessary, and fill into a container together with liquefied orcompressed gas, or dissolving or suspending active substances andsuitable excipients in a solvent, and fill into a container, and fitwith a pump for spraying.

(3) Semi-Solid Preparations for Oro-Mucosal Application

Semi-solid preparations for oro-mucosal application are preparation incream, gel or ointment forms, intended for application to the oralmucosa. Semi-solid preparations for oro-mucosal application are usuallyprepared by emulsifying active substances together with excipients usingpurified water and oil component such as petrolatum, or by homogenizingactive substances together with suitable excipients using polymer gel oroil and fats as the base. Creams are semi-solid preparations, which arein the form of oil-in-water or water-in-oil emulsions. Hydrophobicpreparations in the form of water-in-oil emulsions may be termed “Oilycreams”. Creams are usually prepared by mixing homogeneously andemulsifying an oil-phase component and a water-phase component, bothwarmed, of which either one contains the active substances. Therecomponents have the following constituents. Oil-phase component:Vaseline, fatty alcohols, etc., with or without emulsifying agents orother suitable excipients. Water-phase component: purified water with orwithout emulsifying agents or other suitable excipients. Gels aregelatinous preparations. There are aqueous gels and oily gels. Aqueousgels are usually prepared by adding polymers, other excipients andpurified water to active substances, dissolving or suspending, andgelatinizing by warming and cooling or by adding gelatinizing agents.Oily gels are usually prepared by adding liquid oily bases such asglycols, fatty alcohols and other excipients to active substances andmixing. Ointments are semi-solid preparations, which dissolve ordisperse active substances in a base. There are two types, hydrophobicointments and hydrophilic ointments. Hydrophobic ointments are usuallyprepared by warming to melt hydrophobic bases such as fatty oils, waxesor paraffin, adding and mixing active substances in the base to bedissolved or dispersed, and kneading the whole to make homogeneous.Hydrophilic ointments are usually prepared by warming to melthydrophilic bases such as macrogol, adding and mixing active substancesin the bases, and kneading the whole to make homogenous.

(4) Preparations for Gargle

Preparations for gargle are liquid preparations intended to applylocally to the oral and throat cavities. Solid type preparations to bedissolved in water before use are also included in this category.Preparations for gargle are usually prepared by dissolving activesubstances in a solvent together with suitable excipients, and filteringwhere necessary. Solid preparations are prepared according to saidmethod of tablets or granules.

[Preparation for Injection] (1) Injections

Injections are sterile preparations to be administered directly into thebody through skin, muscle or blood vessel, usually in form of asolution, a suspension or an emulsion of active substances, or of asolid that contains active substances to be dissolved or suspendedbefore use, and include freeze-dried injections, powders, prefilledsyringes, cartridges, parenteral infusions, implants/pellets andprolonged-release injections besides generally called injections.Injections are prepared by the following method (a) and (b):

(a) Dissolve, suspend or emulsify active substances with or withoutexcipients in water for injection or an aqueous or non-aqueous vehiclehomogeneously, fill into containers for injection, seal, and sterilize.(b) Dissolve, suspend or emulsify active substances with or withoutexcipients in water for injection or an aqueous or non-aqueous vehicle,and filtrate aseptically, or prepare aseptically a homogeneous liquid,fill into containers for injection, and seal;Freeze-dried injections are usually prepared by dissolving activesubstances with or without excipients such as diluents in water forinjection, sterilizing the solution by aseptic filtration, filling thefiltrate directly into individual containers for injection and beingfreeze-dried, or dividing the filtrate in special containers, beingfreeze-dried and transferred into individual containers for injection.Powder for injections are usually prepared by filtrating aseptically asolution of active substances, obtaining powders by crystallization fromthe solution or mixing additionally the powders with sterilizedexcipients, and filling the powders into individual containers forinjections. Prefilled syringes for injections are usually prepared bydissolving, suspending or emulsifying active substances with or withoutexcipients in a vehicle, and filling into syringes. Cartridges are usedby fixing in an injection device for exclusive use. Cartridges forinjection are usually prepared by dissolving, suspending or emulsifyingactive substances with or without excipients in a vehicle, and fillinginto cartridges. Parenteral infusions are usually injections of not lessthan 100 mL, intended for intravenous administration. Implants/Pelletsare solid or gel-like form injections, intended for subcutaneous orintramuscular administration by means of an implant device or operativetreatment, for the purpose of releasing active substances for a longperiod of time. Implants/Pellets are usually prepared in a form ofpellet, microsphere or gel using biodegradable polymers. Prolongedrelease injections are injections to be used for intramuscularadministration, for the purpose of releasing active substances for along period of time, and usually prepared by dissolving or suspendingactive substances in a non-aqueous vehicle such as vegetable oil, or bysuspending microspheres prepared with biodegradable polymers.

[Preparations for Dialysis] (1) Dialysis Agents

Dialysis agents are preparations in liquid, or in solid which are to bedissolved before use, intended for peritoneal dialysis or hemodialysis,and include peritoneal dialysis agents and hemodialysis agents.Peritoneal dialysis agents are sterile dialysis agents, intended to beused for peritoneal dialysis, and are usually prepared by dissolvingactive substances with suitable excipients in a vehicle to make acertain volume, or by filling active substances combined with suitableexcipients in a container, and sealing it. Sterilize if necessary. Inthe case of solid preparations to be dissolved before use, it can beprepared according to said preparation method of tablets or granules.Hemodialysis agents are dialysis agents to be used for hemodialysis, andare usually prepared by dissolving active substances with excipients ina vehicle to make a certain volume, or by filling active substances withexcipients in a container. In the case of the solid preparations to bedissolved before use, it can be prepared according to said preparationmethod of tablets or granules.

[Preparation for Inhalation] (1) Inhalations

Inhalations are preparations intended for administration as aerosols tothe bronchial tubes or lung. Inhalations are classified to dry powderinhalers, inhalation liquid preparations and metered-dose inhalers. Drypowder inhalers are preparations which deliver a constant respiratoryintake, intended for administration as solid particle aerosols, and areusually prepared by pulverizing active substances into fine particles.Where necessary, lactose or other suitable excipients are added to makehomogeneous mixture. Inhalation liquid preparations are liquidinhalations which are administered by an inhalation device such asoperating nebulizer. Inhalation liquid preparations are usually preparedby mixing active substances with a vehicle and suitable isotonic agentsand/or pH adjusting agents to make a solution or suspension, and byfiltering where necessary. Metered-dose inhalers are preparations whichdeliver a constant dose of active substances from the container togetherwith propellant filled in. Metered-dose inhalers are usually prepared bydissolving active substances with a suitable dispersing agents andstabilizers in a vehicle to make a solution or suspension, and byfilling in pressure-resistant containers together with liquidpropellant, and setting metering valves.

[Preparation for Ophthalmic Application] (1) Ophthalmic Liquids andSolutions

Ophthalmic liquids and solutions are sterile preparations of liquid, orsolid to be dissolved or suspended before use, intended for applicationto the conjunctival sac or other ocular tissues. Ophthalmic liquids andsolutions are usually prepared by dissolving, suspending activesubstances in a vehicle after adding excipients to make a constantvolume, or mixing active substances and excipients, and filling intocontainers.

(2) Ophthalmic Ointments

Ophthalmic ointments are sterile preparations of semi-solid, intendedfor application to the conjunctival sac and other ocular tissues.Ophthalmic ointments are usually prepared by mixing homogeneouslysolution of or finely powdered active substances with petrolatum orother bases, and filling into containers.

[Preparation for Otic Application] (1) Ear Preparation

Ear preparations are liquid, semi-solid, or solid preparations which areto be dissolved or suspended before use, intended for application to theexternal or internal ear. Ear preparations are usually prepared byfilling in containers with liquids in which active substances andexcipients are dissolved or suspended in a vehicle to make a constantvolume, or with powders in which active substances and excipients aremixed.

[Preparations for Nasal Application] (1) Nasal Preparations

Nasal preparations are preparations intended for application to thenasal cavities or nasal mucous membrane. Nasal preparations areclassified into Nasal dry powder inhalers and Nasal liquid preparations.Nasal dry powder inhalers are fine powdered preparations, intended forapplication to the nasal cavities. Nasal dry powder inhalers are usuallyprepared by pulverizing active substances into moderately fineparticles, or by mixing homogeneously with excipients where necessary.Nasal liquids and solutions are liquid preparations, or solidpreparations to be dissolved or suspended before use, intended forapplication to the nasal cavities. Nasal liquids and solutions areusually prepared by dissolving or suspending active substances in avehicle together with excipients, and filtering where necessary.Isotonic agents and/or pH adjusting agents may be used.

[Preparations for Rectal Application] (1) Suppositories for RectalApplication

Suppositories for rectal application are semi-solid preparations of adesired shape and size, intended for intrarectal application, whichrelease active substances by melting at body temperature or dissolvingor dispersing gradually in the secretions. Suppositories for rectalapplication are usually prepared by mixing homogeneously activesubstances and excipients such as dispersing agents and emulsifyingagents, dissolving or suspending uniformly in a base which is liquefiedby warming, filling a constant volume of the resultant material intocontainers, and molding it into a shape and size. Lipophilic bases orhydrophilic bases are usually used.

(2) Semi-solid preparations for rectal application Semi-solidpreparations for rectal application are preparations which are in a formof cream, gel or ointment intended for application to around or insideof the anus. Semi-solid preparations for rectal application are usuallyprepared by emulsifying active substances with excipients in purifiedwater and oil component such as Vaseline, or by homogeneously mixingactive substances and excipients in a base of polymer gel or grease.Creams for rectal application are usually prepared by mixinghomogeneously and emulsifying an oil-phase component (such as vaseline,fatty alcohols, etc.) and a water phase component (such as purifiedwater with or without emulsifying agents or other suitable excipients),both warmed, of which either one contains the active substances. Gelsfor rectal application are gelatinous preparation. There are aqueousgels and oily gels. Aqueous gels are prepared adding polymers, otherexcipients and purified water to active substances, and dissolving orsuspending, and gelatinizing by warming and cooling or by addinggelatinizing agents. Oily gels are prepared by adding liquid oily basessuch as glycols, fatty alcohols and other excipients to activesubstances and mixing. Ointments for rectal application are semi-solidpreparations, which dissolve or disperse active substances in a base.There are two types, hydrophobic ointment and hydrophilic ointments.Hydrophobic ointments are usually prepared by warming to melthydrophobic bases such as fatty oils, waxes or paraffin, adding andmixing active substances in the bases to be dissolved or dispersed, andkneading the whole to make homogeneous. Hydrophilic ointments areusually prepared by warming to melt hydrophilic bases such as macrogol,adding and mixing active substances in the bases, and kneading the wholeto make homogeneous.

(3) Enemas for Rectal Application

Enemas for rectal application are preparations in liquid form or viscousand gelatinous state, intended for applications via anus. Enemas forrectal application are preparations are usually prepared by dissolvingor suspending active substances in purified water or suitable aqueousvehicle to make a given volume, and filling in containers. Dispersingagents, stabilizers and/or pH adjusting agents may be used.

[Preparations for Vaginal Application] (1) Tablets for Vaginal Use

Tablets for vaginal use are solid applications of a desired shapes andsize, intended for application to the vagina, which release activesubstances by dissolving or dispersing gradually in the secretions.Tablets for vaginal use are usually prepared according to saidpreparation method of tablets.

(2) Suppositories for Vaginal Use Suppositories for vaginal use aresemi-solid preparations of a desired shapes and size, intended forapplication to the vagina, which release active substances by melting atbody temperature or by dissolving or dispersing gradually in thesecretions. Suppositories for vaginal use are usually prepared accordingto said preparation method of suppositories for rectal applications.

[Preparation for Cutaneous Application] (1) Solid Preparations forCutaneous Application

Solid preparations for cutaneous application are solid preparationsintended for application to the skin (including scalp) or nails. Powdersfor cutaneous application are included in this category. Powders forcutaneous application are powdery solid preparations intended forexternal application. Powders for cutaneous application are usuallyprepared by mixing homogeneously active substances and excipients suchas diluents and pulverizing the mixture.

(2) Liquids and Solutions for Cutaneous Application

Liquids and solutions for cutaneous application are liquid preparationsintended for application to the skin (including scalp) or nails.Liniments and lotions are included in this category. Liquids andsolutions for cutaneous application are usually prepared by mixingactive substances and excipients in a vehicle, and filtering ifnecessary. Liniments are liquid or muddy preparations intended forexternal application to the skin by rubbing. Lotions are externalliquids in which active substances are dissolved, emulsified or finelydispersed in an aqueous vehicle. Lotions are usually prepared bydissolving, suspending or emulsifying active substances in purifiedwater with excipients and making homogeneous as a whole.

(3) Spray for Cutaneous Application

Spray for cutaneous application are preparations intended for sprayingactive substances onto the skin in mists, powders, forms or paste state.Spray for cutaneous application are classified into aerosols forcutaneous application and pump sprays for cutaneous application. Sprayfor cutaneous applications are usually prepared by dissolving orsuspending active substances in a vehicle, filtering where necessary,and filling in containers. Aerosols for cutaneous application are sprayswhich atomize active substances together with liquefied or compressedgas filled in containers. Aerosols for cutaneous application are usuallyprepared by dissolving or suspending active substances in a vehicle,filling with liquefied propellants in pressure-resistant containers, andsetting a continuous spray valve. If necessary, dispersing agents andstabilizer may be used. Pump sprays for cutaneous application are sprayswhich atomize active substances in containers by pumping. Pump spraysfor cutaneous application are usually prepared by dissolving orsuspending active substances with excipients in a vehicle, filling incontainers and setting pumps to the containers.

(4) Ointments

Ointments are semi-solid preparations to be applied to the skin, whichdissolve or disperse active substances in a base. There are two types,hydrophobic ointments and hydrophilic ointments. Hydrophobic ointmentsare usually prepared by warming to melt hydrophobic bases such as fattyoils, waxes or paraffin, adding and mixing active substances in the baseto be dissolved or dispersed, and Kneading the whole to makehomogeneous. Hydrophilic ointments are usually prepared by warming tomelt hydrophilic bases such as macrogol, adding and mixing activesubstances in the bases, and kneading the whole to make homogenous.

(5) Creams

Creams are semi-solid preparations to be applied to the skin, which arein the form of oil-in-water or water-in-oil emulsions. Hydrophobicpreparations in the form of water-in-oil emulsions may be termed “Oilycreams”. Creams are usually prepared by mixing homogeneously andemulsifying an oil-phase component and a water-phase component, bothwarmed, of which either one contains the active substances. Therecomponents have the following constituents. Oil-phase component:Vaseline, fatty alcohols, etc., with or without emulsifying agents orother suitable excipients. Water-phase component: purified water with orwithout emulsifying agents or other suitable excipients.

(6) Gels

Gels are gelatinous preparations intended for application to the skin.There are aqueous gels and oily gels. Aqueous gels are usually preparedby adding polymers, other excipients and purified water to activesubstances, dissolving or suspending, and gelatinizing by warming andcooling or by adding gelatinizing agents. Oily gels are usually preparedby adding liquid oily bases such as glycols, fatty alcohols and otherexcipients to active substances and mixing.

(7) Patches

Patches are preparations intended to be attached on the skin. Patchesare classified into Tapes/Plasters and Cataplasms/Gel patches. Patchesare usually prepared by mixing active substances homogeneously with abase such as a polymer or a mixture of polymers, spreading on a backinglayer or liner, and cutting into a given size. Percutaneous absorptiontype preparations may be prepared by using a release rate-controllingmembrane. Where necessary, adhesive agents or penetration enhancers maybe used. Tapes/Plasters are patches which are prepared with bases ofpractically no water contain. Tapes/Plasters are usually prepared bymixing homogeneously active substances with or without excipients and abase of non water-soluble natural or synthetic polymers such as resins,plastics or rubber, and spreading on a cloth or spreading and sealing ona cloth or plastic film, cutting into a given size. The preparations maybe also prepared by filling a mixture of active substances and a basewith or without other excipients in releasers composed with arelease-controlling film, supporter and liner. Cataplasms/Gels arepatches using water containing bases. Cataplasms/Gels patches areusually prepared by mixing active substances, purified water, andglycerin or other liquid materials, or by mixing and kneading natural orsynthetic polymers, which are soluble in water or absorbent of water,with purified water, adding active substances, mixing the wholehomogeneously, spreading on a cloth or film, and cutting into a givensize.

Unless otherwise defined, all technical and scientific terms, and allabbreviations used in this specification have the meaning as normallyunderstood by a skilled person in the art to which the present inventionpertains.

The contents of the all patent documents and non-patent documents, andthe contents of the reference documents explicitly cited herein areincorporated herein as a part of the specification.

EXAMPLES

The present invention is described below in greater detail by way ofExamples. It is to be noted that the present invention is not limited bythe following descriptions.

The solvents in parentheses shown in connection with the separationpositions in chromatography and with TLC represent the eluting solventsor developing solvents used. The proportions are volume ratios.

The solvents in parentheses shown in connection with NMR represent thesolvents used for measurement.

As a rule, the compound names used in this specification are based onthe computer program ACD/Name® or the Chemdraw Ultra (version 12.0,Cambridge Soft), which generate chemical names according to IUPAC rules.The compound names are also based on the IUPAC nomenclature.

Reference Example 1: 4-Methylenechromane

A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(hereinafter, “THF”) (1.3 mol/L, 931 mL) was dropped into a 1,500-mL THFsolution of methyltriphenylphosphonium bromide (435 g) under a stream ofnitrogen on ice, and the mixture was stirred at room temperature for 1h. The mixture was further stirred at room temperature for 1 h afterdropping a 180-mL THF solution of 4-chromanone (150 g) at −5° C. Afteradding a saturated ammonium chloride aqueous solution to the reactionmixture on ice, the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was then purified by silica gel column chromatography to obtainthe title compound (75.9 g) having the following physical propertyvalues.

TLC: Rf 0.62 (hexane:ethyl acetate=9:1); ¹H-NMR (CDCl₃): δ2.59-2.75,4.18-4.31, 4.89, 5.51, 6.79-6.94, 7.12-7.20, 7.56.

Reference Example 2: Ethyl(2′R,4S)-2,3-dihydrospiro[chromene-4,1′-cyclopropane]-2′-carboxylate

Under a stream of nitrogen, a dichloro(p-cymene)ruthenium(II) dimer(15.8 g), and (S,S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine (15.6g) were added to a dichloromethane solution (2,500 mL) of the compound(75.9 g) produced in Reference Example 1. A dichloromethane solution(150 mL) of diazoethyl acetate (containing 13% of dichloromethane, 134g) was then slowly dropped at room temperature, and the mixture wasstirred for 1 h. After adding a saturated ammonium chloride aqueoussolution to the reaction mixture, the mixture was extracted withdichloromethane, and the organic layer was dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas then purified by silica gel column chromatography to obtain thetitle compound (91.2 g) having the following physical property values.

¹H-NMR (CDCl₃): δ 1.26, 1.54-1.67, 2.07-2.22, 4.05-4.21, 4.27, 6.68,6.78-6.89, 7.04-7.12.

Reference Example 3:(2′R,4S)-2,3-Dihydrospiro[chromene-4,1′-cyclopropane]-2′-carboxylic acid

An aqueous solution (160 mL) of lithium hydroxide monohydrate (29.6 g)was added to a methanol (400 mL) and 1,2-dimethoxyethane (400 mL)solution of the compound (91.2 g) produced in Reference Example 2, andthe mixture was stirred overnight at room temperature. A 10% aqueoussolution of citric acid was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was thenrecrystallized with dichloromethane to obtain the title compound (55.2g) having the following physical property values.

¹H-NMR (CDCl₃): δ 1.59-1.67, 1.68-1.76, 2.15, 2.21-2.29, 4.12-4.23,4.25-4.36, 6.70, 6.80-6.92, 7.06-7.16;

HPLC retention time: 6.9 min (CHIRALPAK IC 4.6 mm×250 mm hexane:ethylacetate:formic acid=97:3:1).

Reference Example 4: Methyl(2′R,4S)-2,3-dihydrospiro[chromene-4,1′-cyclopropane]-2′-carboxylate

Under a stream of nitrogen, potassium carbonate (28.5 g) was added to anN,N-dimethylformamide (hereinafter, “DMF”) solution (200 mL) of thecompound (40.0 g) produced in Reference Example 3. The mixture wasstirred overnight at room temperature after dropping iodomethane (31.9g). The reaction mixture was poured into ice water, and extracted with ahexane-ethyl acetate mixed solution. The organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain the title compound (40.1g) having the following physical property values.

TLC: Rf 0.30 (hexane:ethyl acetate=9:1);

¹H-NMR (CDCl₃): δ1.57-1.69, 2.09-2.22, 3.71, 4.07-4.17, 4.27, 6.68,6.78-6.90, 7.04-7.14.

Reference Example 5: Methyl(2′R,4S)-6-iodo-2,3-dihydrospiro[chromene-4,1′-cyclopropane]-2′-carboxylate

Under a stream of nitrogen, 1,3-diiodo-5,5-dimethylhydantoin (35.6 g),and three droplets of concentrated sulfuric acid were added to amethanol solution (320 mL) of the compound (40.1 g) produced inReference Example 4, on ice. The mixture was stirred for 1.5 h under thesame condition, and for 2.5 h at room temperature. The reaction mixturewas diluted with a hexane-ethyl acetate mixed solution, and washed witha saturated sodium bicarbonate aqueous solution. The aqueous layer wasextracted with a hexane-ethyl acetate mixed solution. The organic layerwas washed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain the titlecompound (63.8 g) having the following physical property values.

TLC: Rf 0.33 (hexane:ethyl acetate=9:1);

¹H-NMR (CDCl₃): δ1.60, 2.06-2.19, 3.71, 4.09, 4.20-4.31, 6.59, 6.93,7.36.

Reference Example 6:(2′R,4S)-6-Iodo-2,3-dihydrospiro[chromene-4,1′-cyclopropane]-2′-carboxylicacid

A sodium hydroxide aqueous solution (2 mol/L, 44 mL) was added to amethanol (60 mL) and 1,2-dimethoxyethane (60 mL) solution of thecompound (15.0 g) produced in Reference Example 5, and the mixture wasstirred at room temperature for 1.5 h. After adding hydrochloric acid tothe reaction mixture, the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toobtain the title compound (14.4 g) having the following physicalproperty values.

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.57-1.74, 2.11, 2.16-2.25, 4.10-4.20, 4.23-4.33,6.59, 6.94, 7.37.

Reference Example 7: Ethyl 4-(4-formyl-2-nitrophenyl)butanoate

Iodine (26.0 g) was added to a 700-mL solution of a zinc powder (99.2 g)in N,N-dimethylacetamide (hereinafter, “DMA”) under a stream ofnitrogen, and the mixture was stirred for 10 min. After dropping ethyl4-bromobutyrate (200 g), the mixture was stirred at 80° C. for 2 h toprepare a zinc reagent. Under a stream of nitrogen,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (7.14 g), and palladiumacetate (1.96 g) were added to a 500-mL THF solution of3-nitro-4-bromobenzaldehyde (100 g), and the zinc reagent (500 mL) wasdropped into the mixture on ice. This was followed by stirring at roomtemperature for 30 min. A saturated ammonium chloride aqueous solution,and water were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was thenpurified by silica gel column chromatography to obtain the titlecompound (91.2 g) having the following physical property values.

TLC: Rf 0.61 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ1.27, 1.97-2.09, 2.42, 3.01, 4.15, 7.57, 8.04, 8.38,10.03.

Reference Example 8: Ethyl 4-(4-cyano-2-nitrophenyl)butanoate

Hydroxylamine hydrochloride (26.0 g) was added to a 350-mL DMF solutionof the compound (92.0 g) produced in Reference Example 7, and themixture was stirred at 50° C. for 1 h. The mixture was stirred at 90° C.for 2 h after adding acetyl chloride (30 mL). Then, water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with water, a saturated sodium bicarbonateaqueous solution, and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas then purified by silica gel column chromatography to obtain thetitle compound (81.0 g) having the following physical property values.

TLC: Rf 0.65 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.27, 1.92-2.10, 2.37-2.45, 2.91-3.06, 4.15, 7.55,7.81, 8.21.

Reference Example 9: Ethyl 4-(2-amino-4-cyanophenyl)butanoate

Palladium carbon (50% wet, 8.0 g) was added to an 80-mL ethanol solutionof the compound (17.0 g) produced in Reference Example 8, and themixture was stirred at room temperature for 9 h in a hydrogenatmosphere. After filtering the reaction mixture with Celite (tradename), the filtrate was concentrated to obtain the title compound (12.0g) having the following physical property values.

TLC: Rf 0.56 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.28, 1.79-1.95, 2.38-2.45, 2.50-2.60, 4.09-4.30,6.89, 6.93-6.98, 7.04-7.10.

Reference Example 10: Ethyl4-[4-cyano-2-({[(2′R,4S)-6-iodo-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoate

4-Methylmorpholine (24.0 mL), 4-dimethylaminopyridine (5.33 g), and apropylphosphonic acid anhydride cyclic trimer (hereinafter, “T3P”; 1.7mol/L, 46.5 mL) were added to a 90-mL DMA solution of the compound (14.4g) produced in Reference Example 6, and the compound (10.0 g) producedin Reference Example 9, and the mixture was stirred overnight at roomtemperature. Ethyl acetate, water, and a hydrochloric acid aqueoussolution were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with water, asaturated sodium bicarbonate aqueous solution, and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was then washed with a hexane-ethylacetate mixed solution to obtain the title compound (19.3 g) having thefollowing physical property values.

TLC: Rf 0.42 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.20, 1.61, 1.66-1.79, 1.83, 2.18-2.28, 2.39-2.49,2.60, 3.66, 3.90, 4.00-4.12, 4.26, 6.58, 7.05, 7.15-7.22, 7.26-7.31,7.33, 8.72, 9.39.

Reference Example 11:(2′R,4S)-2′-{[5-Cyano-2-(4-ethoxy-4-oxobutyl)phenyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropane]-6-carboxylicacid

Sodium acetate (3.35 g), and a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (555 mg) were added to a 60-mL DMF solution ofthe compound (7.40 g) produced in Reference Example 10, and the mixturewas stirred at 80° C. for 6 h in a carbon monoxide atmosphere. Apotassium carbonate aqueous solution was added to the reaction mixture,and the mixture was stirred for some time. After adding tert-butylmethyl ether and water, the mixture was filtered with Celite (tradename). A hydrochloric acid aqueous solution was added to the filtrate,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas then purified by silica gel column chromatography (YamazenAutopurification Device) to obtain the title compound (6.14 g) havingthe following physical property values.

TLC: Rf 0.48 (dichloromethane:ethyl acetate:methanol=8:4:1);

¹H-NMR (CDCl₃): δ 1.08, 1.65-1.80, 1.83-1.92, 2.25-2.36, 2.37-2.49,2.55-2.66, 2.71, 3.55, 3.79, 4.12-4.23, 4.37, 6.88, 7.15-7.22,7.27-7.32, 7.61, 7.83, 8.73, 9.40.

Reference Example 12: Ethyl4-[4-cyano-2-({[(2′R,4S)-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoate

The title compound (53.0 mg) having the following physical propertyvalues was obtained by performing the procedures of Reference Example10, except that the compound (60.0 mg) produced in Reference Example 11was used instead of the compound produced in Reference Example 6, andthat methylamine hydrochloride (87.5 mg) was used instead of thecompound produced in Reference Example 9.

¹H-NMR (CDCl₃): δ 1.07, 1.64-1.79, 1.81-1.89, 2.20-2.35, 2.40, 2.60,2.69, 2.98, 3.44-3.59, 3.68-3.83, 4.07-4.19, 4.27-4.38, 6.05, 6.82,7.15-7.22, 7.27-7.32, 7.35-7.44, 8.72, 9.37.

Example 1:4-[4-Cyano-2-({[(2′R,4S)-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound (45 mg) having the following physical propertyvalues was obtained by performing the procedures of Reference Example 6using the compound (53 mg) produced in Reference Example 12. Ethanol wasused instead of methanol.

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.21-1.30, 1.55, 1.65-1.82, 2.06-2.26, 2.38-2.67,2.67-2.76, 3.02, 3.57, 4.33, 4.49-4.58, 6.25, 6.81, 7.19, 7.23-7.30,7.94, 8.87, 9.93.

Example 2

The present compounds having the following physical property values wereobtained by performing the same procedures from Reference Example 12 toExample 1, except that the methylamine hydrochloride was replaced with acorresponding amine compound.

Example 2-1:4-{4-Cyano-2-[({(2′R,4S)-6-[(cyclopropylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 0.23-0.31, 0.52-0.63, 0.96-1.14, 1.22-1.30, 1.55,1.66-1.81, 2.06-2.24, 2.38-2.66, 2.66-2.76, 3.31, 3.57, 4.34, 4.49-4.59,6.31, 6.83, 7.19, 7.24-7.29, 7.32, 7.95, 8.87, 9.93.

Example 2-2:4-{4-Cyano-2-[({(2′R,4S)-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.51 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.26, 1.55, 1.67-1.84, 2.06-2.27, 2.39-2.67,2.67-2.78, 3.39, 3.51-3.78, 4.33, 4.49-4.59, 6.62, 6.82, 7.19,7.24-7.29, 7.32, 7.92, 8.86, 9.88.

Example 2-3:4-{4-Cyano-2-[({(2′R,4S)-6-[(2-methyl-2-propanyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid

TLC: Rf 0.63 (chloroform:methanol=19:1);

¹H-NMR (DMSO-d₆): δ1.37, 1.57, 1.64-1.85, 2.04-2.25, 2.42-2.48,2.60-2.71, 4.01-4.15, 4.24-4.38, 6.80, 7.34-7.45, 7.52-7.66, 7.88, 9.89,12.11.

Example 2-4:4-[4-Cyano-2-({[(2′R,4S)-6-{[(2S)-1-methoxy-2-propanyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.62 (ethyl acetate:methanol=19:1);

¹H-NMR (CD₃OD): δ 1.22, 1.65-1.89, 2.12-2.26, 2.33, 2.62-2.77,3.30-3.32, 3.37, 3.41, 3.47, 4.21-4.39, 6.82, 7.37-7.51, 7.58, 8.05.

Example 2-5:4-{4-Cyano-2-[({(2′R,4S)-6-[(1-methyl-1H-pyrazol-4-yl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.51 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.61, 1.66-1.87, 2.08-2.25, 2.50, 2.59-2.73, 3.81,4.06-4.19, 4.28-4.42, 6.90, 7.41, 7.49-7.61, 7.73, 7.88, 7.99, 9.91,10.19, 12.10.

Example 2-6:4-{4-Cyano-2-[({(2′R,4S)-6-[(3-methoxy-1-azetidinyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.54 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ1.56, 1.67-1.80, 2.04-2.26, 2.45, 2.58-2.72, 3.21,3.74-3.91, 4.06-4.27, 4.30, 4.37-4.51, 6.83, 7.15, 7.34-7.44, 7.57,7.88, 9.89, 12.11.

Example 2-7: 4-{4-Cyano-2-[({(2′R,4S)-6-[(1,3-oxazol-2-ylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.64 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.53-1.63, 1.65-1.83, 2.07-2.25, 2.48, 2.58-2.70,4.03-4.16, 4.27-4.40, 4.47-4.64, 6.87, 7.15, 7.40, 7.48, 7.56, 7.67,7.87, 8.04, 9.02, 9.90, 12.10.

Example 2-8:4-[4-Cyano-2-({[(2′R,4S)-6-(1,3-oxazol-2-ylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.40 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.61, 1.66-1.80, 1.86, 2.11-2.25, 2.52, 2.61-2.72,4.14, 4.38, 6.93, 7.19, 7.42, 7.54-7.65, 7.76, 7.88, 7.96, 9.92, 11.38,12.10.

Example 2-9:4-{4-Cyano-2-[({(2′R,4S)-6-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.62 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.59, 1.67-1.81, 1.92, 2.10-2.25, 2.54, 2.60-2.72,3.77, 4.12, 4.35, 6.59, 6.89, 7.42, 7.55-7.62, 7.68, 7.77, 7.88, 9.92,10.75, 12.10.

Example 2-10:4-[4-Cyano-2-({[(2′R,4S)-6-(cyclopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.65 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 0.49-0.59, 0.65-0.75, 1.58, 1.66-1.82, 2.06-2.26,2.47, 2.61-2.71, 2.81, 4.09, 4.34, 6.83, 7.36-7.45, 7.54-7.65, 7.88,8.30, 9.89, 12.09.

Example 2-11:4-[2-({[(2′R,4S)-6-(Butylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)-4-cyanophenyl]butanoicacid

TLC: Rf 0.79 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 0.93-1.00, 1.21-1.83, 2.06-2.25, 2.37-2.77, 3.41-3.50,3.51-3.63, 4.33, 4.54, 6.18, 6.81, 7.15-7.31, 7.94, 8.87, 9.93.

Example 2-12: 4-[4-Cyano-2-({[(2′R,4S)-6-(cyclohexylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.86 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 1.10-1.87, 1.94-2.26, 2.38-2.79, 3.50-3.64, 3.85-4.04,4.33, 4.54, 6.04, 6.81, 7.14-7.31, 7.93, 8.87, 9.93.

Example 2-13:4-[4-Cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.74 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 1.27, 1.34-1.92, 2.01-2.30, 2.38-2.80, 3.50-3.61,4.18-4.43, 4.54, 6.00, 6.81, 7.15-7.31, 7.94, 8.87, 9.93.

Example 2-14:4-[4-Cyano-2-({[(2′R,4S)-6-(cyclopentylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.83 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 1.20-1.86, 2.00-2.26, 2.38-2.79, 3.50-3.64, 4.25-4.45,4.46-4.61, 6.13, 6.81, 7.13-7.31, 7.94, 8.87, 9.93.

Example 2-15: 4-[4-Cyano-2-({[(2′R,4S)-6-(isobutylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phen yl]butanoicacid

TLC: Rf 0.83 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 0.84-1.03, 1.21-2.01, 2.06-2.26, 2.37-2.79, 3.20-3.38,3.51-3.62, 4.34, 4.49-4.59, 6.18-6.32, 6.82, 7.14-7.32, 7.94, 8.87,9.93.

Example 2-16:4-{2-[({(2′R,4S)-6-[(2S)-2-Butanylcarbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]-4-cyanophenyl}butanoicacid

TLC: Rf 0.84 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 0.95, 1.18-1.91, 2.05-2.25, 2.39-2.78, 3.50-3.64,4.03-4.20, 4.33, 4.48-4.60, 5.97, 6.81, 7.13-7.32, 7.94, 8.87, 9.93.

Example 2-17:4-{2-[({(2′R,4S)-6-[(2R)-2-Butanylcarbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]-4-cyanophenyl}butanoicacid

TLC: Rf 0.84 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 0.98, 1.18-1.32, 1.49-1.86, 2.05-2.25, 2.39-2.81,3.57, 4.11, 4.33, 4.54, 5.95, 6.81, 7.13-7.33, 7.93, 8.81, 8.86, 9.93.

Example 2-18:4-[2-({[(2′R,4S)-6-(Benzylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)-4-cyanophenyl]butanoicacid

TLC: Rf 0.84 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 1.20-1.86, 2.06-2.26, 2.40-2.79, 3.58, 4.34,4.48-4.72, 6.47, 6.80, 7.15-7.42, 7.99, 8.87, 9.92.

Example 2-19:4-{4-Cyano-2-[({(2′R,4S)-6-[(3R)-tetrahydro-3-furanylcarbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.56 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.59, 1.67-1.83, 1.90, 2.07-2.26, 2.46, 2.61-2.71,3.58, 3.72, 3.82-3.92, 4.10, 4.33, 4.48, 6.85, 7.38-7.48, 7.58, 7.67,7.88, 8.39, 9.91, 12.11.

Example 2-20:4-{4-Cyano-2-[({(2′R,4S)-6-[(trans-4-hydroxycyclohexyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.57 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 0.77-1.85, 1.95-2.26, 2.38-2.77, 3.48-3.77, 3.83-4.04,4.33, 4.54, 5.97, 6.81, 7.15-7.35, 7.92, 8.87, 9.92.

Example 2-21: 4-{4-Cyano-2-[({(2′R,4S)-6-[(cis-4-hydroxycyclohexyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid

TLC: Rf 0.64 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.20-1.31, 1.51-1.86, 2.05-2.24, 2.38-2.79, 3.51-3.62,3.94-4.09, 4.33, 4.54, 6.16, 6.82, 7.13-7.31, 7.92, 8.87, 9.92.

Example 2-22:4-[4-Cyano-2-({[(2′R,4S)-6-{[2-(dimethylamino)ethyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.17 (ethyl acetate:methanol=9:1, Chromatorex diol TLC plate(Fuji Silysia Chemical Ltd.));

¹H-NMR (CDCl₃): δ 1.19-1.34, 1.59, 1.66-1.84, 2.09-3.16, 3.38,3.62-3.81, 4.33, 4.52, 6.85, 7.15-7.31, 7.52-7.64, 7.87, 8.80, 9.55.

Example 2-23:4-[4-Cyano-2-({[(2′R,4S)-6-(2-pyridinylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.83 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ1.58, 1.73, 1.88-1.99, 2.10-2.24, 2.60-2.70,4.06-4.18, 4.30-4.40, 6.90, 7.14, 7.41, 7.57, 7.72, 7.77-7.90, 8.18,8.38, 9.91, 10.78, 12.09.

Example 2-24:4-{4-Cyano-2-[({(2′R,4S)-6-[(2-pyridinylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.62 (ethyl acetate:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.58, 1.63-1.84, 2.01-2.24, 2.59-2.69, 4.04-4.16,4.27-4.39, 4.55, 6.87, 7.22-7.33, 7.40, 7.55, 7.66-7.80, 7.87,8.45-8.55, 9.01, 9.90, 12.09.

Example 2-25:4-[4-Cyano-2-({[(2′R,4S)-6-{[(2R)-1-methoxy-2-propanyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.76 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.12, 1.59, 1.67-1.83, 2.08-2.25, 2.47, 2.61-2.70,3.23-3.31, 3.40, 4.09, 4.20, 4.33, 6.85, 7.39-7.46, 7.58, 7.65, 7.89,8.09, 9.90, 12.11.

Example 2-26:4-{4-Cyano-2-[({(2′R,4S)-6-[(3-oxetanylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.56 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.59, 1.66-1.80, 2.09-2.25, 2.46, 2.61-2.71, 3.15,3.52, 4.10, 4.28-4.39, 4.63, 6.85, 7.37-7.47, 7.57-7.64, 7.89, 8.50,9.92, 12.10.

Example 2-27:4-{4-Cyano-2-[({(2′R,4S)-6-[(3S)-tetrahydro-3-furanylcarbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.50 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.51-1.63, 1.64-1.97, 2.04-2.28, 2.41-2.47,2.60-2.70, 3.58, 3.64-3.77, 3.80-3.92, 4.02-4.16, 4.26-4.38, 4.38-4.53,6.84, 7.36-7.48, 7.58, 7.67, 7.87, 8.37, 9.91, 12.10.

Example 2-28:4-{4-Cyano-2-[({(2′R,4S)-6-[(cyclobutylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.63 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.52-1.62, 1.62-1.88, 1.88-2.06, 2.06-2.24,2.60-2.70, 3.23-3.30, 4.01-4.14, 4.26-4.37, 6.83, 7.36-7.45, 7.59, 7.88,8.31, 9.91, 12.10.

Example 2-29:4-[4-Cyano-2-({[(2′R,4S)-6-(3-pyridazinylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.65 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.59, 1.72, 1.87-1.99, 2.05-2.24, 2.54-2.70,4.05-4.23, 4.30-4.44, 6.93, 7.41, 7.57, 7.72, 7.76-7.93, 8.38, 9.00,9.99, 11.45, 12.11.

Example 2-30:4-{4-Cyano-2-[({(2′R,4S)-6-[(1-methyl-4-piperidinyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.21 (dichloromethane:methanol:28% ammonia water=4:1:0.1);

¹H-NMR (DMSO-d₆): δ1.49-1.83, 1.90-2.06, 2.06-2.24, 2.65, 2.81, 3.73,4.02-4.15, 4.26-4.37, 6.83, 7.37-7.46, 7.56, 7.63, 7.90, 8.14, 10.01.

Example 2-31:4-[4-Cyano-2-({[(2′R,4S)-6-(1H-pyrazol-4-ylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

¹H-NMR (CD₃OD): δ 1.65-1.90, 2.24, 2.35, 2.60-2.80, 4.20-4.42, 6.89,7.39-7.50, 7.59, 7.70, 7.89, 8.03.

Example 2-32:4-{4-Cyano-2-[({(2′R,4S)-6-[(2,2-difluoroethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.76 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.53-1.81, 2.06-2.25, 2.41-2.47, 2.58-2.71,3.55-3.78, 4.04-4.17, 4.25-4.40, 5.84-6.36, 6.87, 7.41, 7.48, 7.55,7.67, 7.87, 8.73, 9.91, 12.10.

Example 2-33:4-[4-Cyano-2-({[(2′R,4S)-6-{[(3S)-1-methyl-3-pyrrolidinyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.33 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.50-1.59, 1.62-1.84, 2.06-2.23, 2.37, 2.64,2.74-2.84, 4.14, 4.24-4.36, 4.45, 6.83, 7.35-7.48, 7.55, 7.63, 7.98,8.45, 10.09.

Example 2-34:4-[4-Cyano-2-({[(2′R,4S)-6-(1,3-thiazol-2-ylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.68 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.56-1.64, 1.65-1.81, 1.86-1.96, 2.10-2.24,2.60-2.70, 4.07-4.19, 4.32-4.43, 6.94, 7.26, 7.41, 7.53-7.60, 7.79,7.82-7.90, 9.92, 12.11, 12.53.

Example 2-35:4-[4-Cyano-2-({[(2′R,4S)-6-(3-pyridinylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.58-1.65, 1.72, 1.83, 2.08-2.24, 2.61-2.70,4.30-4.43, 6.94, 7.35-7.45, 7.57, 7.79, 7.88, 8.11-8.18, 8.30, 8.90,9.93, 10.24, 12.09.

Example 2-36:4-[4-Cyano-2-({[(2′R,4S)-6-(2-pyrimidinylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.53-1.63, 1.63-1.80, 1.84-1.95, 2.07-2.24,2.60-2.70, 4.06-4.19, 4.29-4.43, 6.90, 7.24, 7.41, 7.57, 7.64, 7.75,7.86, 8.72, 9.91, 10.94, 12.08.

Example 2-37:4-[4-Cyano-2-({[(2′R,4S)-6-(1,2-oxazol-3-ylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.65 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.36-1.50, 1.62, 1.86-2.15, 2.53-2.68, 2.68-2.89,4.19-4.37, 6.85, 6.91, 7.31-7.41, 7.41-7.49, 7.62, 7.79, 8.36, 8.75,11.61, 12.62.

Example 2-38: 4-[4-Cyano-2-({[(2′R,4S)-6-(cyclobutylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.72 (ethyl acetate);

¹H-NMR (CD₃OD): δ 1.62-1.90, 2.02-2.44, 2.59-2.80, 4.19-4.30, 4.33,4.49, 6.82, 7.37-7.51, 7.58, 8.04.

Example 2-39:4-[4-Cyano-2-({[(2′R,4S)-6-{[1-(2-methyl-2-propanyl)-1H-pyrazol-4-yl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.64 (ethyl acetate);

¹H-NMR (CD₃OD): δ 1.59, 1.67-1.92, 2.16-2.29, 2.30-2.41, 2.62-2.78,4.21-4.32, 4.33-4.46, 6.88, 7.37-7.51, 7.58, 7.65-7.74, 8.03, 8.11.

Example 2-40:4-[4-Cyano-2-({[(2′R,4S)-6-(tetrahydro-2H-pyran-4-ylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.62 (ethyl acetate:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.44-1.86, 2.02-2.24, 2.59-2.70, 3.35-3.44,3.80-4.15, 4.25-4.37, 6.84, 7.37-7.46, 7.57, 7.64, 7.87, 8.13, 9.90,12.09.

Example 2-41:4-[4-Cyano-2-({[(2′R,4S)-6-(1,2-oxazol-5-ylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.71 (ethyl acetate:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.56-1.66, 1.73, 1.87, 2.06-2.25, 2.60-2.70,4.06-4.19, 4.31-4.44, 6.39, 6.94, 7.41, 7.57, 7.67, 7.81, 7.87, 8.50,9.92, 11.90, 12.09.

Example 2-42:4-[4-Cyano-2-({[(2′R,4S)-6-(4-pyridinylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.53 (dichloromethane:methanol=4:1);

¹H-NMR (DMSO-d₆): δ1.57-1.66, 1.73, 1.83, 2.09-2.24, 2.60-2.70,4.08-4.21, 4.31-4.42, 6.95, 7.41, 7.52-7.61, 7.74-7.91, 8.42-8.52, 9.91,10.38, 12.09.

Example 2-43:4-{4-Cyano-2-[({(2′R,4S)-6-[(1-methyl-1H-pyrazol-5-yl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.58 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.55-1.65, 1.66-1.90, 2.06-2.29, 2.50, 2.60-2.74,3.66, 4.06-4.22, 4.30-4.46, 6.17, 6.93, 7.35-7.45, 7.52-7.61, 7.77,7.88, 9.91, 10.15, 12.10.

Example 2-44:4-[4-Cyano-2-({[(2′R,4S)-6-(propylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.75 (ethyl acetate);

¹H-NMR (DMSO-d₆): δ0.88, 1.45-1.63, 1.68-1.82, 2.07-2.25, 2.45,2.61-2.72, 3.15-3.26, 4.10, 4.32, 6.85, 7.39-7.46, 7.57-7.63, 7.88,8.32, 9.90, 12.11.

Example 2-45:4-{4-Cyano-2-[({(2′R,4S)-6-[(2-ethoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (DMSO-d₆): δ 1.11, 1.59, 1.67-1.83, 2.07-2.26, 2.47, 2.61-2.71,3.35-3.52, 4.10, 4.33, 6.85, 7.38-7.48, 7.57-7.64, 7.88, 8.42, 9.90,12.09.

Example 2-46:4-[4-Cyano-2-({[(2′R,4S)-6-(ethylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.59 (ethyl acetate);

¹H-NMR (DMSO-d₆): δ 1.10, 1.58, 1.65-1.80, 2.07-2.24, 2.45, 2.58-2.69,3.19-3.33, 4.09, 4.32, 6.84, 7.37-7.45, 7.57, 7.62, 7.88, 8.33, 9.89,12.09.

Example 2-47:4-{4-Cyano-2-[({(2′R,4S)-6-[(1-methoxy-2-methyl-2-propanyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.72 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ 1.33, 1.57, 1.67-1.86, 2.08-2.25, 2.47, 2.62-2.71,3.27, 3.53, 4.09, 4.32, 6.82, 7.35-7.45, 7.48, 7.57-7.62, 7.88, 9.89,12.10.

Reference Example 13: Ethyl4-[4-cyano-2-({[(2′R,4S)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoate

Triethylamine (60 μL), and T3P (a 1.7 mol/L ethyl acetate solution, 95μL) were added at room temperature to a 0.5-mL dichloromethane solutionof the compound (50 mg) produced in Reference Example 11, andacetylhydrazine (16 mg). The reaction mixture was stirred at roomtemperature for 1.5 h, and concentrated under reduced pressure. TheBurgess reagent (methyl N-(triethylammoniosulfonyl)carbamate, 117 mg)was added at room temperature to a 5-mL THF solution of the compoundobtained by purifying the resulting residue by silica gel columnchromatography (Yamazen Autopurification Device). The mixture wasstirred at 100° C. for 1 h using a microwave reactor (Biotage, Ltd.). Asaturated sodium bicarbonate aqueous solution was poured into thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was then purified by silica gel column chromatography(Yamazen Autopurification Device) to obtain the title compound (22 mg)having the following physical property values.

TLC: Rf 0.53 (hexane:ethyl acetate=1:3);

¹H-NMR (CDCl₃): δ 0.94, 1.65-1.83, 1.89, 2.26-2.34, 2.35-2.44,2.56-2.63, 2.66-2.76, 3.12-3.28, 3.36-3.55, 3.58-3.74, 4.07-4.23,4.30-4.41, 6.92, 7.18, 7.28, 7.54, 7.70, 8.72, 9.39.

Example 3:4-[4-Cyano-2-({[(2′R,4S)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 13, instead of the compound produced inReference Example 12.

TLC: Rf 0.93 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): 1.27, 1.54, 1.70-1.91, 2.17, 2.32, 2.45-2.90, 3.64,4.35-4.48, 4.56-4.66, 6.92, 7.20, 7.28, 7.58, 8.15, 8.92, 9.91, 12.68.

Example 4

The present compounds having the following physical property values wereobtained by performing the same procedures from Reference Example 13 toExample 1, except that the acetylhydrazine was replaced with acorresponding hydrazine compound.

Example 4-1:4-[4-Cyano-2-({[(2′R,4S)-6-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.64 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): 1.14-1.32, 1.78, 2.07-2.41, 2.43-2.91, 3.63, 4.33-4.49,4.61, 6.86-6.96, 7.16-7.32, 7.54, 8.13, 8.92, 9.91.

Example 4-2:4-{4-Cyano-2-[({(2′R,4S)-6-[5-(2-methyl-2-propanyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.83 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 1.19-1.32, 1.44-1.52, 1.64-1.87, 2.10-2.40, 2.44-2.90,3.64, 4.35-4.49, 4.56-4.67, 6.93, 7.16-7.35, 7.60, 8.15, 8.92, 9.92.

Example 4-3:4-[4-Cyano-2-({[(2′R,4S)-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.32, 1.60, 1.66-1.82, 2.10-2.24, 2.60-2.70, 2.92,4.09-4.21, 4.31-4.42, 6.99, 7.41, 7.46, 7.57, 7.71, 7.88, 9.91, 12.08.

Reference Example 14: Ethyl4-[4-cyano-2-({[(2′R,4S)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoate

Triethylamine (0.144 mL), and T3P (a 1.7 mol/L ethyl acetate solution,0.380 mL) were added at room temperature to a 0.5-mL ethyl acetatesolution of the compound (80 mg) produced in Reference Example 11, andacetamideoxime (32 mg). The reaction mixture was heated under reflux for4 days, and concentrated under reduced pressure. The resulting residuewas then purified by silica gel column chromatography (YamazenAutopurification Device) to obtain the title compound (49 mg) having thefollowing physical property values. TLC: Rf 0.55 (hexane:ethylacetate=1:1);

¹H-NMR (CDCl₃): δ 0.92, 1.64-1.83, 1.86-1.95, 2.22-2.35, 2.36-2.44,2.45, 2.54-2.65, 2.72, 3.39-3.54, 3.59-3.73, 4.10-4.23, 4.32-4.44, 6.94,7.20, 7.28, 7.59, 7.84, 8.74, 9.39.

Example 5:4-[4-Cyano-2-({[(2′R,4S)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 14, instead of the compound produced inReference Example 12.

TLC: Rf 0.74 (ethyl acetate:methanol=20:1);

¹H-NMR (DMSO-d₆): δ 1.55-1.64, 1.67-1.83, 2.11-2.29, 2.39, 2.51-2.60,2.61-2.73, 4.11-4.25, 4.31-4.44, 7.02, 7.41, 7.52-7.62, 7.83, 7.88,9.90, 12.10.

Reference Example 15: Ethyl4-[4-cyano-2-({[(2′R,4S)-6-(4-fluorophenyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoate

Cesium carbonate (84 mg), 4-fluorophenylboronic acid (36 mg), andpurified water (0.4 mL) were added at room temperature to a 0.4-mL1,2-dimethoxyethane solution of the compound (70 mg) produced inReference Example 10. After replacing the atmosphere with argon, a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (5 mg) was added, and the mixture was stirredovernight at 85° C. The reaction mixture was diluted with ethyl acetate,and extracted with ethyl acetate after adding water. The organic layerwas washed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas then purified by silica gel column chromatography (YamazenAutopurification Device) to obtain the title compound (54 mg) having thefollowing physical property values.

TLC: Rf 0.48 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 0.83, 1.64-1.79, 1.82-1.93, 2.29, 2.33-2.43,2.48-2.74, 3.30, 3.49, 4.06-4.19, 4.26-4.38, 6.84-6.91, 6.97, 7.04-7.15,7.15-7.22, 7.22-7.32, 7.39-7.51, 8.73, 9.30.

Example 6:4-[4-Cyano-2-({[(2′R,4S)-6-(4-fluorophenyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 15, instead of the compound produced inReference Example 12.

TLC: Rf 0.58 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.50-1.60, 1.72, 1.87, 2.06-2.24, 2.60-2.69,4.03-4.15, 4.24-4.35, 6.87, 7.11, 7.19-7.29, 7.32-7.44, 7.56, 7.61-7.70,7.87, 9.88, 12.09.

Example 7

The present compounds having the following physical property values wereobtained by performing the same procedures from Reference Example 15 toExample 1, except that the 4-fluorophenylboronic acid was replaced witha corresponding boronic acid compound, or a corresponding heterocyclicring.

Example 7-1:4-[4-Cyano-2-({[(2′R,4S)-6-phenyl-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.53 (dichloromethane:methanol=9:1)

¹H-NMR (CDCl₃): δ 1.58-1.81, 2.14-2.27, 2.36-2.46, 2.49-2.71, 2.78,4.22-4.37, 6.92, 7.15, 7.16-7.22, 7.26-7.51, 7.52-7.61, 8.69, 8.95.

Example 7-2:4-[4-Cyano-2-({[(2′R,4S)-6-(4-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.36 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.52-1.63, 1.64-1.79, 1.87-1.99, 2.08-2.30,2.43-2.73, 3.99-4.20, 4.25-4.41, 6.93, 7.31, 7.40, 7.56, 7.66-7.71,7.87, 8.51-8.62, 9.88, 11.90-12.18.

Example 7-3:4-[4-Cyano-2-({[(2′R,4S)-6-(3-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.36 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.56, 1.65-1.77, 1.88-2.00, 2.06-2.30, 2.34-2.75,4.03-4.19, 4.25-4.39, 6.92, 7.22, 7.37-7.51, 7.57, 7.87, 7.99-8.09,8.48-8.53, 8.87, 9.87.

Example 7-4:4-[4-Cyano-2-({[(2′R,4S)-6-(1H-pyrazol-1-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.23-1.34, 1.62, 1.66-1.83, 2.05-2.23, 2.40-2.59,2.61-2.82, 3.37-3.47, 4.22-4.35, 4.44-4.52, 6.49, 6.88, 7.11, 7.20,7.28, 7.41, 7.71, 8.86, 9.95.

Example 7-5:4-[4-Cyano-2-({[(2′R,4S)-6-(1H-pyrazol-5-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.35 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.51-1.62, 1.63-1.86, 2.04-2.33, 2.34-2.75,3.98-4.14, 4.23-4.35, 6.65, 6.82, 7.29, 7.40, 7.48-7.60, 7.63, 7.87,9.91, 12.47.

Example 7-6:4-[4-Cyano-2-({[(2′R,4S)-6-(4-pyridazinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): 51.53-1.62, 1.63-1.80, 1.95-2.06, 2.09-2.33,2.34-2.78, 4.01-4.22, 4.28-4.42, 6.97, 7.42, 7.47, 7.57, 7.71, 7.87,7.94-8.04, 9.20, 9.60, 9.87, 12.1.

Example 7-7:4-[4-Cyano-2-({[(2′R,4S)-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.25 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): 1.44-1.88, 2.22-2.33, 2.48, 2.58-2.76, 3.70, 4.16-4.36,6.81-6.95, 7.11-7.34, 7.39, 7.56, 8.73, 9.16.

Example 7-8:4-[4-Cyano-2-({[(2′R,4S)-6-(5-pyrimidinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.57, 1.65-1.79, 1.92-2.03, 2.06-2.35, 2.36-2.77,4.01-4.17, 4.27-4.40, 6.94, 7.33, 7.40, 7.50-7.61, 7.87, 9.12, 9.86,12.08.

Example 7-9:4-[4-Cyano-2-({[(2′R,4S)-6-(2-thienyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.51-1.61, 1.65-1.78, 1.79-1.88, 2.05-2.31,2.40-2.76, 3.98-4.14, 4.23-4.36, 6.83, 7.04-7.16, 7.30-7.49, 7.57, 7.86,9.90, 12.08.

Example 7-10:4-[4-Cyano-2-({[(2′R,4S)-6-(2-oxo-1-pyrrolidinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.50-1.59, 1.60-1.80, 1.93-2.12, 2.19, 2.31-2.51,2.54-2.78, 3.78, 3.93-4.09, 4.19-4.31, 6.78, 7.09, 7.29, 7.40, 7.56,7.85, 9.91, 12.08.

Example 7-11:4-[4-Cyano-2-({[(2′R,4S)-6-(1,3-thiazol-5-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.53 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 1.20-1.30, 1.58, 1.73-1.90, 2.26-2.37, 2.52,2.64-2.82, 4.19-4.41, 6.81-6.97, 7.13-7.35, 7.77, 8.60, 8.69, 9.25.

Example 7-12:4-[4-Cyano-2-({[(2′R,4S)-6-(pyrazolo[1,5-a]pyridin-3-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.59-1.70, 1.76-1.84, 2.31, 2.43-2.53, 2.60-2.80,4.15-4.44, 6.72, 6.89, 6.97, 7.09-7.36, 7.68, 7.89, 8.43, 8.70, 9.15.

Example 7-13:4-[4-Cyano-2-({[(2′R,4S)-6-(6-methoxy-3-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.56 (ethyl acetate);

¹H-NMR (CD₃OD): δ 1.65-1.93, 2.14-2.29, 2.33, 2.58, 2.67-2.78, 3.92,4.21, 4.32, 6.80-6.91, 7.06, 7.30, 7.42, 7.48, 7.84-7.95, 8.31.

Example 7-14:4-{4-Cyano-2-[({(2′R,4S)-6-[6-(1H-pyrazol-1-yl)-3-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.60 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.57, 1.63-1.79, 1.89-2.01, 2.08-2.25, 2.50-2.56,2.60-2.72, 4.03-4.18, 4.27-4.40, 6.59, 6.93, 7.27, 7.40, 7.47-7.60,7.80-7.91, 7.96, 8.27, 8.63, 8.76, 9.88, 12.10.

Example 7-15:4-{4-Cyano-2-[({(2′R,4S)-6-[6-(dimethylamino)-3-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.58 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.51-1.62, 1.63-1.80, 1.84-1.95, 2.06-2.25,2.51-2.57, 2.60-2.75, 3.18, 4.02-4.17, 4.23-4.39, 6.88, 7.01-7.21,7.35-7.47, 7.55, 7.87, 8.10-8.29, 9.92, 12.10.

Example 7-16:4-[4-Cyano-2-({[(2′R,4S)-6-(6-methyl-3-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.63 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.46-1.56, 1.56-1.79, 2.03, 2.16, 2.66, 4.15,4.22-4.33, 6.86, 7.20, 7.27, 7.33-7.44, 7.44-7.52, 8.08-8.21, 8.70,11.11.

Example 7-17:4-[4-Cyano-2-({[(2′R,4S)-6-(6-fluoro-3-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.59 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.52-1.60, 1.65-1.79, 1.93, 2.07-2.23, 2.60-2.70,4.03-4.15, 4.27-4.37, 6.90, 7.19-7.27, 7.40, 7.45, 7.56, 7.87, 8.25,8.51, 9.87, 12.09.

Example 7-18:4-{4-Cyano-2-[({(2′R,4S)-6-[6-(methylsulfonyl)-3-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid

TLC: Rf 0.57 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.58, 1.72, 1.92-2.01, 2.09-2.24, 2.60-2.70,4.06-4.17, 4.30-4.40, 6.96, 7.33-7.45, 7.58, 7.88, 8.06, 8.41, 9.09,9.90, 12.10.

Example 7-19:4-[4-Cyano-2-({[(2′R,4S)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.51-1.61, 1.65-1.80, 1.91, 2.09-2.24, 2.60-2.70,4.09, 4.25-4.36, 6.47, 6.89, 7.18, 7.38-7.45, 7.45-7.50, 7.56, 7.88,8.17, 8.47, 9.94, 11.65, 12.06.

Example 7-20:4-[4-Cyano-2-({[(2′R,4S)-6-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.65 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.48-1.58, 1.65-1.79, 1.88, 2.06-2.14, 2.19,2.59-2.70, 3.03, 3.40-3.47, 3.99-4.11, 4.19-4.33, 6.81, 7.03, 7.23,7.29, 7.40, 7.56, 7.86, 7.95, 9.87, 12.08.

Example 7-21:4-{4-Cyano-2-[({(2′R,4S)-6-[6-(methylamino)-3-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.52-1.61, 1.72, 1.84-1.94, 2.06-2.23, 2.60-2.70,2.94, 4.02-4.13, 4.25-4.36, 6.88, 6.99, 7.14, 7.34-7.43, 7.56, 7.86,8.09-8.21, 9.91, 12.13, 13.60.

Example 7-22:4-{4-Cyano-2-[({(2′R,4S)-6-[3-(2-hydroxy-2-propanyl)phenyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.46, 1.54-1.62, 1.72, 1.79-1.88, 2.07-2.24,2.60-2.70, 4.02-4.15, 4.25-4.36, 5.05, 6.88, 7.09, 7.29-7.46, 7.57,7.66, 7.87, 9.90, 12.09.

Example 7-23:4-[4-Cyano-2-({[(2′R,4S)-6-(2-oxo-1-azetidinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.47 (dichloromethane:methanol=20:1);

¹H-NMR (DMSO-d₆): δ 1.54-1.79, 2.02-2.11, 2.19, 2.39-2.68, 3.01-3.05,3.55-3.61, 3.95-4.03, 4.20-4.29, 6.77-6.81, 7.16, 7.41, 7.56, 7.85,9.90, 12.10.

Example 7-24:4-[4-Cyano-2-({[(2′R,4S)-6-(2-oxo-1,3-oxazolidin-3-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.47 (dichloromethane:methanol=20:1);

¹H-NMR (DMSO-d₆): 1.54-1.79, 2.05-2.24, 2.39-2.68, 3.96-4.06, 4.23-4.31,4.36-4.45, 6.81, 7.01, 7.27, 7.41, 7.56, 7.86, 9.92, 12.10.

Example 7-25:4-{4-Cyano-2-[({(2′R,4S)-6-[(4R)-4-hydroxy-2-oxo-1-pyrrolidinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=20:1);

¹H-NMR (DMSO-d₆): δ 1.53-1.80, 2.06-2.13, 2.19, 2.37-2.81, 3.47-3.55,4.00-4.08, 4.20-4.39, 5.29-5.37, 6.78, 7.14, 7.25, 7.40, 7.55, 7.87,9.91, 12.10.

Example 7-26:4-{4-Cyano-2-[({(2′R,4S)-6-[4-(methylsulfonyl)phenyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.58, 1.72, 1.92, 2.08-2.24, 2.60-2.70, 3.23,4.05-4.17, 4.27-4.39, 6.93, 7.25, 7.41, 7.50, 7.57, 7.84-7.99, 9.88,12.09.

Example 7-27:4-[4-Cyano-2-({[(2′R,4S)-6-(4-cyanophenyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.58 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.56, 1.72, 1.93, 2.08-2.24, 2.59-2.69, 4.04-4.16,4.27-4.38, 6.92, 7.25, 7.40, 7.51, 7.56, 7.87, 9.86, 12.08.

Example 7-28:4-[4-Cyano-2-({[(2′R,4S)-6-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.59 (chloroform:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.51-1.61, 1.64-1.88, 2.08-2.28, 2.39-2.46,2.58-2.71, 3.82, 4.05-4.17, 4.27-4.39, 6.32, 6.90, 7.00, 7.25,7.37-7.45, 7.55, 7.86, 9.89, 12.10.

Reference Example 16: Ethyl4-{4-cyano-2-[({(2′R,4S)-6-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoate

The title compound having the following physical property values wasobtained by performing the procedures of Reference Example 15 using a1-(2-tetrahydropyranyl)-1H-pyrazole-4-boronic acid pinacol ester,instead of 4-fluorophenylboronic acid.

TLC: Rf 0.62 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 0.86, 1.64-1.79, 1.82-1.90, 2.02-2.16, 2.21-2.29,2.34-2.43, 2.52-2.72, 3.28-3.42, 3.45-3.60, 3.65-3.80, 4.03-4.16,4.25-4.40, 5.35-5.45, 6.81, 6.90, 7.13-7.23, 7.28, 7.71, 7.76, 8.74,9.36.

Example 8:4-[4-Cyano-2-({[(2′R,4S)-6-(1H-pyrazol-4-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

A hydrochloric acid 1,4-dioxane solution (4 mol/L, 0.1 mL) was added atroom temperature to a 1-mL 1,4-dioxane solution of the compound (30 mg)produced in Reference Example 16. The reaction mixture was stirred at60° C. for 3 h. After concentrating the reaction mixture under reducedpressure, the procedures of Example 1 was performed to obtain thepresent compound having the following physical property values.

TLC: Rf 0.40 (ethyl acetate:methanol=20:1);

¹H-NMR (DMSO-d₆): δ 1.55, 1.64-1.79, 1.81-1.92, 2.04-2.27, 2.35-2.47,2.52-2.74, 4.02, 4.27, 6.76, 7.09, 7.32, 7.40, 7.56, 7.85, 7.99, 9.89.

Reference Example 17: Ethyl4-[4-cyano-2-({[(2′R,4S)-6-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoate

While replacing the atmosphere with argon, potassium acetate (1.44 g),bis(pinacolato)diboron (2.43 g), and a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (300 mg) were added to a 40-mL dimethylsulfoxide solution of the compound (4.00 g) produced in ReferenceExample 10, and the mixture was stirred at 90° C. for 4 h. Afterdiluting the reaction mixture with ethyl acetate, water was added, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas then purified by silica gel column chromatography (YamazenAutopurification Device) to obtain the title compound (3.54 g) havingthe following physical property values.

TLC: Rf 0.37 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.01, 1.20-1.29, 1.31, 1.63-1.77, 1.84, 2.18-2.27,2.33-2.42, 2.53-2.60, 3.20-3.34, 3.45-3.60, 4.00-4.10, 4.25-4.37, 6.78,7.18, 7.28, 7.52, 8.68, 9.37.

Example 9:4-[4-Cyano-2-({[(2′R,4S)-6-(2-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

While replacing the atmosphere with argon, 2-bromopyridine (36 μL),cesium carbonate (120 mg), and a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (7.5 mg) were added to a solution of thecompound (100 mg) of Reference Example 17 in 1,2-dimethoxyethane (0.3mL) and water (0.3 mL), and the mixture was stirred at 95° C. for 17 h.The reaction mixture was extracted with ethyl acetate, and the organiclayer was washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (YamazenAutopurification Device) to obtain ethyl4-[4-cyano-2-({[(2′R,4S)-6-(2-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoate,and the procedures of Example 1 were performed with this compound toobtain the present compound having the following physical propertyvalues.

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.54-1.66, 1.68-1.88, 2.07-2.29, 2.54-2.76,4.04-4.17, 4.26-4.38, 6.89, 7.23-7.33, 7.40, 7.52-7.64, 7.77-7.99, 8.61,9.90, 12.10.

Example 10

The present compounds having the following physical property values wereobtained by performing the same procedures performed in Example 9,except that the 2-bromopyridine was replaced with a correspondinghalogen-containing heterocyclic ring.

Example 10-1:4-[4-Cyano-2-({[(2′R,4S)-6-(2-pyrimidinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.54-1.83, 2.07-2.28, 2.35-2.77, 4.05-4.22,4.26-4.42, 6.93, 7.29-7.45, 7.56, 7.88, 7.94, 8.15, 8.84, 9.93, 12.10.

Example 10-2:4-[4-Cyano-2-({[(2′R,4S)-6-(1,3-thiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.81 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 1.19-1.32, 1.34-1.85, 2.10-2.25, 2.40-2.79, 3.61,4.35, 4.48-4.62, 6.88, 7.15-7.30, 7.35, 7.38-7.47, 7.68-7.77, 7.85,8.88, 10.00.

Example 10-3:4-[4-Cyano-2-({[(2′R,4S)-6-(1,3-oxazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.81 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 1.18-1.29, 1.53, 1.68-1.86, 2.09-2.33, 2.43-2.87,3.60, 4.39, 4.52-4.64, 6.90, 7.15, 7.17, 7.28, 7.67, 7.72, 8.05, 8.92,9.95.

Example 10-4:4-[4-Cyano-2-({[(2′R,4S)-6-(1-methyl-1H-1,2,3-triazol-4-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.58 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 1.21-1.32, 1.56, 1.69-1.86, 2.14-2.31, 2.44-2.88,3.64, 4.15-4.20, 4.34, 4.53, 6.86, 7.13-7.31, 7.63, 7.68, 7.79, 8.92,10.01.

Example 10-5:4-[4-Cyano-2-({[(2′R,4S)-6-(3-pyridazinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.17-1.31, 1.61, 1.66-1.90, 2.11-2.32, 2.36-2.82,3.48-3.71, 4.35, 4.54, 6.98, 7.21, 7.28, 7.36, 7.66, 7.83, 7.80-7.83,8.87, 9.15, 10.07.

Example 10-6:4-[4-Cyano-2-({[(2′R,4S)-6-(2-pyrazinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.25, 1.61, 1.68-1.88, 2.08-2.29, 2.40-2.87, 3.49,4.25-4.41, 4.52, 6.97, 7.21, 7.29, 7.46, 7.61, 8.45, 8.62, 8.85, 8.97,9.93.

Example 10-7:4-{4-Cyano-2-[({(2′R,4S)-6-[5-(methylsulfonyl)-2-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.61, 1.73, 1.80-1.92, 2.07-2.28, 2.38-2.75, 3.34,4.06-4.20, 4.26-4.44, 6.96, 7.41, 7.57, 7.71, 7.88, 7.97, 8.18-8.36,9.06, 9.91, 12.08.

Example 10-8:4-{4-Cyano-2-[({(2′R,4S)-6-[5-(hydroxymethyl)-2-pyridinyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.51-1.62, 1.63-1.87, 2.07-2.30, 2.53-2.75,4.03-4.19, 4.25-4.39, 4.54, 5.29, 6.88, 7.40, 7.52-7.64, 7.70-7.94,8.53, 9.92, 12.07.

Example 10-9:4-[4-Cyano-2-({[(2′R,4S)-6-(5-fluoro-2-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.64 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.53-1.64, 1.65-1.88, 2.06-2.32, 2.40-2.80,4.00-4.19, 4.24-4.40, 6.89, 7.40, 7.51-7.65, 7.71-7.84, 7.88, 8.00-8.05,8.60, 9.92, 12.08.

Example 10-10:4-[4-Cyano-2-({[(2′R,4S)-6-(6-methoxy-2-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.53-1.64, 1.66-1.79, 1.79-1.91, 2.03-2.30,2.40-2.79, 3.94, 4.02-4.16, 4.26-4.40, 6.70, 6.89, 7.40, 7.48-7.62,7.73, 7.80-7.89, 9.89, 12.07.

Example 10-11:4-[4-Cyano-2-({[(2′R,4S)-6-(5-methoxy-2-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.70 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.16-1.30, 1.57, 1.70-1.83, 2.04-2.27, 2.52,2.59-2.73, 2.74-2.92, 3.54, 3.92, 4.30, 4.48, 6.89, 7.19, 7.24-7.31,7.38, 7.49, 7.52, 8.18, 8.83, 10.06.

Example 10-12:4-[4-Cyano-2-({[(2′R,4S)-6-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.69 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.19-1.31, 1.56, 1.70-1.88, 2.12-2.32, 2.42-2.84,3.54, 4.37, 4.56, 6.92, 7.16-7.31, 7.71-7.82, 8.91, 9.84.

Example 11:4-(4-Cyano-2-{[(2′R,4S)-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carbonyl]amino}phenyl)butanoic acid

The present compound having the following physical property values wasobtained by performing the same procedures from Reference Example 10 toExample 1 using the compound produced in Reference Example 9, and thecompound produced in Reference Example 3.

TLC: Rf 0.62 (chloroform:methanol=9:1);

¹H-NMR (CD₃OD): δ 1.66, 1.77-1.91, 2.08-2.28, 2.34, 2.48, 2.71, 4.16,4.28, 6.74, 6.82-6.91, 7.06, 7.42, 7.48, 7.91.

Reference Example 18:(2′R,4S)-2′-{[2-(4-Ethoxy-4-oxobutyl)-5-fluorophenyl]carbamoyl}-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-6-carboxylicacid

The title compound having the following physical property values wasobtained by performing the same procedures of Reference Example7→Reference Example 9→Reference Example 10→Example 1, except that5-fluoro-2-iodonitrobenzene was used instead of3-nitro-4-bromobenzaldehyde.

¹H-NMR (DMSO-d₆): δ 1.12, 1.52-1.77, 2.12, 2.26, 2.51-2.62, 3.87-4.02,4.12, 4.34, 6.86, 6.92, 7.20, 7.41, 7.47, 7.68, 9.68, 12.68.

Example 12

The present compounds having the following physical property values wereobtained by performing the same procedures from Reference Example 12 toExample 1 using the compound produced in Reference Example 18 instead ofthe compound produced in Reference Example 11, using methylaminehydrochloride or a corresponding amine compound.

Example 12-1:4-[4-Fluoro-2-({[(2′R,4S)-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.69 (ethyl acetate:methanol=19:1);

¹H-NMR (CD₃OD): δ1.62-1.87, 2.12-2.28, 2.32, 2.56-2.78, 2.90, 4.23,4.34, 6.76-6.89, 7.20, 7.38-7.51, 7.54.

Example 12-2: 4-{4-Fluoro-2-[({(2′R,4S)-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.67 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.51-1.79, 2.06-2.22, 2.41-2.61, 3.25, 3.36-3.46,4.07, 4.31, 6.83, 6.95, 7.19, 7.33, 7.43, 7.63, 8.42, 9.74, 12.06.

Example 12-3:4-{4-Fluoro-2-[({(2′R,4S)-6-[(1-methyl-1H-pyrazol-4-yl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.64 (ethyl acetate:methanol=9:1);

¹H-NMR (CD₃OD): δ 1.66-1.86, 2.12-2.37, 2.57-2.70, 3.88, 4.25, 4.37,6.81-6.92, 7.21, 7.45, 7.58, 7.63, 7.68, 8.00.

Reference Example 19: Ethyl4-(2-{[(1R,2R)-6′-(benzyloxy)-2′,3′-dihydrospiro[cyclopropane-1,1′-indene]-2-carbonyl]amino}-4-cyanophenyl)butanoate

The title compound having the following physical property values wasobtained by performing the procedures of Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 10, using6-(benzyloxy)-2,3-dihydro-1H-inden-1-one instead of 4-chromanone.

¹H-NMR (CDCl₃): δ 1.25, 1.38-1.45, 1.68-1.81, 1.82-1.87, 2.32-2.46,2.57-2.67, 2.86-3.08, 3.82-3.92, 3.97-4.07, 5.00, 6.46, 6.77, 7.12,7.17, 7.25-7.31, 7.32-7.43, 8.78, 9.15.

Example 13:4-[2-({[(1R,2R)-6′-(Benzyloxy)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)-4-cyanophenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 19, instead of the compound produced inReference Example 12.

TLC: Rf 0.53 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.36-1.43, 1.66-1.77, 1.79-1.85, 2.31, 2.42-2.73,2.84-3.09, 5.05, 6.49, 6.81, 7.13-7.21, 7.24-7.30, 7.32-7.47, 8.72,8.92.

Example 14:4-[4-Cyano-2-({[(1R,2R)-6′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoicacid

10% Palladium/carbon (12 mg) was added to a solution of the compound (40mg) of Example 13 in ethyl acetate (3 mL) and 1,4-dioxane (1 mL). Afterreplacing the atmosphere with hydrogen, the mixture was stirred at roomtemperature for 9 h. The reaction mixture was filtered using Celite, andthe filtrate was concentrated under reduced pressure. The resultingresidue was then purified by silica gel column chromatography to obtainthe present compound (32 mg) having the following physical propertyvalues.

TLC: Rf 0.40 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.36-1.43, 1.65-1.85, 2.32, 2.47-2.55, 2.58-2.76,2.83-3.08, 6.37, 6.62, 7.06, 7.22, 7.25-7.37, 8.74, 8.92.

Reference Example 20: Ethyl4-(4-cyano-2-{[(1R,2R)-6′-hydroxy-2′,3′-dihydrospiro[cyclo propane-1,1′-indene]-2-carbonyl]amino}phenyl)butanoate

The present compound having the following physical property values wasobtained by performing the procedures of Example 14 using the compoundproduced in Reference Example 19, instead of the compound produced inExample 13. ¹H-NMR (CDCl₃): δ 1.24, 1.38-1.43, 1.70-1.87, 2.31-2.49,2.58-2.67, 2.85-3.07, 3.89-4.01, 4.04-4.16, 4.49, 6.31, 6.58, 7.04,7.17, 7.26-7.31, 8.78, 9.18.

Reference Example 21: Ethyl4-[4-cyano-2-({(1R,2R)-6′-[(1-methyl-1H-pyrazol-4-yl)methoxy]-2′,3′-dihydrospiro[cyclopropane-1,1′-indene]-2-carbonyl}amino)phenyl]butanoate

Under a stream of nitrogen, cyanomethylenetributylphosphorane (0.06 mL)was dropped into a 0.2-mL toluene solution of the compound (30 mg)produced in Reference Example 20, and (1-methylpyrazol-4-yl)methanol(9.6 mg), and the mixture was stirred overnight at 100° C. The reactionmixture was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (7 mg) having the following physical property values.

¹H-NMR (CDCl₃): δ 1.26, 1.39-1.42, 1.68-1.85, 2.28-2.51, 2.55-2.65,2.83-3.05, 3.87-4.01, 4.04-4.18, 4.89, 6.40, 6.72-6.79, 7.06-7.38, 7.41,7.51, 8.77, 9.13.

Example 15: 4-{4-Cyano-2-[({(1R,2R)-6′-[(1-methyl-1H-pyrazol-4-yl)methoxy]-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl}carbonyl)amino]phenyl}butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 21, instead of the compound produced inReference Example 12.

TLC: Rf 0.26 (dichloromethane:methanol=20:1);

¹H-NMR (DMSO-d₆): 1.45-1.57, 1.66-1.79, 2.13-2.25, 2.26-2.75, 2.84-2.92,3.81, 4.90, 6.51, 6.77, 7.09, 7.39, 7.47, 7.55, 7.77, 7.96.

Reference Example 22: Ethyl4-[4-cyano-2-({(1R,2R)-6′-[2-(methylamino)-2-oxoethoxy]-2′,3′-dihydrospiro[cyclopropane-1,1′-indene]-2-carbonyl}amino)phenyl]butanoate

Potassium carbonate (33 mg) and tetrabutylammonium iodide (4.4 mg), andsubsequently 2-chloro-N-methylacetamide (25.7 mg) were added at roomtemperature to a 0.5-mL DMF solution of the compound (50 mg) produced inReference Example 20, and the reaction mixture was stirred overnight at50° C. The reaction mixture was diluted with ethyl acetate, and, afteradding a saturated ammonium chloride aqueous solution and water,extracted with ethyl acetate. The organic layer was washed with waterand 20% brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was then purified bysilica gel column chromatography (Yamazen Autopurification Device) toobtain the title compound (51 mg) having the following physical propertyvalues.

TLC: Rf 0.26 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 1.19, 1.39-1.44, 1.68-1.84, 1.86-1.89, 2.27-2.70,2.84-3.08, 3.79-3.93, 3.95-4.06, 4.07, 4.44, 6.38, 6.55, 6.70,7.13-7.20, 7.26-7.30, 8.75, 9.07.

Example 16:4-{4-Cyano-2-[({(1R,2R)-6′-[2-(methylamino)-2-oxoethoxy]-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl}carbonyl)amino]phenyl}butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 22, instead of the compound produced inReference Example 12.

TLC: Rf 0.59 (ethyl acetate:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.44-1.51, 1.56, 2.07-2.34, 2.66, 2.87, 6.54, 6.76,7.12, 7.41, 7.56, 7.92, 8.01, 9.75, 12.12.

Example 17:4-{4-Cyano-2-[({(1R,2R)-6′-[2-(dimethylamino)-2-oxoethoxy]-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl}carbonyl)amino]phenyl}butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures from Reference Example 22 toExample 1, using 2-chloro-N,N-dimethylacetamide instead of2-chloro-N-methylacetamide.

TLC: Rf 0.54 (ethyl acetate:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.47-1.58, 1.71, 2.08-2.32, 2.33-2.70, 2.82-2.91,3.00, 4.74, 6.49, 6.70, 7.10, 7.41, 7.57, 7.91, 9.79, 12.16.

Reference Example 23: Ethyl4-[4-cyano-2-({(1R,2R)-6′-[(trifluoromethanesulfonyl)oxy]-2′,3′-dihydrospiro[cyclopropane-1,1′-indene]-2-carbonyl}amino)phenyl]butanoate

In a nitrogen atmosphere, triethylamine (0.1 mL), and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfoneamide(128 mg) were added to a 2-mL dichloromethane solution of the compound(100 mg) produced in Reference Example 20, and the mixture was stirredat room temperature for 3 h. The mixture was further stirred at roomtemperature for 2 h after adding1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfoneamide(128 mg) to the reaction liquid. The reaction liquid was then purifiedby silica gel column chromatography to obtain the title compound (130mg) having the following physical property values.

¹H-NMR (CDCl₃): δ 1.22-1.29, 1.39-1.44, 1.70-1.83, 1.86-1.91, 2.34-2.51,2.60-2.67, 2.95-3.14, 3.90-4.02, 4.05-4.16, 6.67, 7.03, 7.19, 7.21-7.31,8.78, 9.19.

Reference Example 24:(1R,2R)-2-{[5-Cyano-2-(4-ethoxy-4-oxobutyl)phenyl]carbamoyl}-2′,3′-dihydrospiro[cyclopropane-1,1′-indene]-6′-carboxylicacid

The compound (120 mg) produced in Reference Example 23 was dissolved inDMSO (3 mL), and ultrasonically deaerated under reduced pressure. To thereaction liquid were then added 1,3-bis(diphenylphosphino)propane (dppp;18 mg), palladium(II) acetate (10 mg), lithium chloride (92 mg), sodiumformate (148 mg), diisopropylethylamine (0.34 mL), and an aceticanhydride (0.19 mL). The mixture was stirred at 90° C. for 4 h whilereplacing the atmosphere with carbon monoxide. After adding a 0.1 Nhydrochloric acid aqueous solution, the reaction mixture was extractedwith ethyl acetate, and the organic layer was dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was then purified by silica gel column chromatography to obtainthe title compound (40 mg) having the following physical propertyvalues.

¹H-NMR (CDCl₃): δ 1.18, 1.44-1.51, 1.64-1.79, 1.85-1.90, 2.35-2.48,2.57-2.78, 2.99-3.17, 3.84-3.91, 4.03-4.11, 7.18, 7.24-7.36, 7.52, 7.89,8.81, 9.29.

Example 18

The present compounds having the following physical property values wereobtained by performing the procedures from Reference Example 12 toExample 1 using the compound produced in Reference Example 24 instead ofthe compound produced in Reference Example 11, using methylaminehydrochloride or a corresponding amine compound.

Example 18-1: 4-[4-Cyano-2-({[(1R,2R)-6′-(methylcarbamoyl)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.29 (dichloromethane:methanol=20:1);

¹H-NMR (CDCl₃): δ 1.26-1.31, 1.66-1.78, 1.82-1.87, 2.23-2.30, 2.34-2.48,2.52-2.71, 2.91-3.03, 3.04, 3.13-3.27, 6.21-6.29, 7.17, 7.19-7.35, 7.70,8.82, 9.56.

Example 18-2:4-{4-Cyano-2-[({(1R,2R)-6′-[(2-methoxyethyl)carbamoyl]-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.50 (dichloromethane:methanol=20:1);

¹H-NMR (CDCl₃): δ 1.25-1.31, 1.65-1.77, 1.81-1.86, 2.23-2.30, 2.35-2.47,2.51-2.71, 2.91-3.03, 3.13-3.27, 3.41, 3.54-3.78, 6.62-6.67, 7.17,7.19-7.30, 7.34, 7.66, 8.82, 9.51.

Example 18-3:4-{4-Cyano-2-[({(1R,2R)-6′-[(1-methyl-1H-pyrazol-4-yl)carbamoyl]-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.28 (dichloromethane:methanol=20:1);

¹H-NMR (CDCl₃): δ 1.26-1.34, 1.68-1.78, 1.81-1.88, 2.25-2.31, 2.43-2.72,2.95-3.06, 3.17-3.23, 3.92, 7.16-7.33, 7.42, 7.52, 7.75, 7.86, 7.99,8.83, 9.54.

Example 19:4-[4-Cyano-2-({[(1R,2R)-6′-(3-pyridinyl)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures from Reference Example 15 toExample 1 using the compound produced in Reference Example 23.Pyridine-3-boronic acid was used instead of 4-fluorophenylboronic acid.

TLC: Rf 0.30 (dichloromethane:methanol=20:1);

¹H-NMR (CD₃OD): δ 1.58-1.66, 1.75-1.90, 2.25-2.45, 2.47-2.55, 2.68-2.79,3.07-3.16, 7.15, 7.34-7.56, 7.98, 8.10, 8.52, 8.78.

Reference Example 25:(2′R,4S)-2′-{[5-Cyano-2-(4-ethoxy-4-oxobutyl)phenyl]carbamoyl}-7-fluoro-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-6-carboxylicacid

The title compound having the following physical property values wasobtained by performing the procedures of Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4→Reference Example5→Reference Example 6→Reference Example 10→Reference Example 11, using7-fluorochroman-4-one instead of 4-chromanone.

¹H-NMR (CDCl₃): δ 1.13, 1.66-1.78, 1.84-1.90, 2.25-2.35, 2.42-2.47,2.58-2.67, 3.60-3.73, 3.78-3.90, 4.10-4.22, 4.35-4.44, 6.60, 7.19,7.26-7.33, 7.50, 8.71, 9.37.

Example 20

The present compounds having the following physical property values wereobtained by performing the procedures from Reference Example 12 toExample 1 using the compound produced in Reference Example 25 instead ofthe compound produced in Reference Example 11, using methylaminehydrochloride or a corresponding amine compound.

Example 20-1:4-[4-Cyano-2-({[(2′R,4S)-7-fluoro-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.74 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ1.18-1.29, 1.50-1.62, 1.70-1.80, 2.05-2.15, 2.20-2.27,2.44-2.76, 3.03, 3.54-3.60, 4.31-4.40, 4.54-4.59, 6.57, 6.82-6.95, 7.20,7.24-7.33, 8.06, 8.88, 9.94.

Example 20-2:4-{4-Cyano-2-[({(2′R,4S)-7-fluoro-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.49 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.19-1.26, 1.58-1.64, 1.68-1.84, 2.05-2.29, 2.45-2.77,3.39, 3.53-3.64, 3.65-3.72, 4.31-4.43, 4.54-4.62, 6.57, 7.17-7.34, 8.05,8.88, 9.93.

Example 20-3:4-[4-Cyano-2-({[(2′R,4S)-6-(ethylcarbamoyl)-7-fluoro-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.62 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ 1.09, 1.55, 1.65-1.78, 2.02-2.28, 2.47, 2.60-2.71,3.17-3.33, 4.12, 4.33, 6.73, 7.19, 7.41, 7.56, 7.88, 8.07, 9.89, 12.11.

Example 20-4:4-[4-Cyano-2-({[(2′R,4S)-7-fluoro-6-(propylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.56 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ0.87, 1.42-1.58, 1.62-1.78, 2.04-2.23, 2.42,2.60-2.69, 3.11-3.23, 4.12, 4.31, 6.73, 7.18, 7.41, 7.56, 7.88, 8.06,9.90, 12.11.

Example 20-5:4-[4-Cyano-2-({[(2′R,4S)-7-fluoro-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.68 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ 1.13, 1.53, 1.63-1.79, 2.02-2.24, 2.46, 2.61-2.69,3.96-4.18, 4.33, 6.72, 7.14, 7.41, 7.56, 7.80-7.92, 9.89, 12.11.

Example 21:4-[4-Cyano-2-({[(2′R,4S)-6-fluoro-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 10→Example 1 using6-fluoro-4-chromanone instead of 4-chromanone.

TLC: Rf 0.38 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.46-1.80, 2.18-2.24, 2.48-2.75, 4.09-4.32, 6.55,6.75-6.87, 7.21, 7.25-7.34, 8.66, 9.00.

Reference Example 26: Ethyl4-(2-{[(2′R,4S)-6-benzoyl-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carbonyl]amino}-4-cyanophenyl)butanoate

Phenylboronic acid (10 mg), potassium carbonate (22 mg), and a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (9 mg) were added to a 1-mL anisole solution ofthe compound (30 mg) produced in Reference Example 10, and the mixturewas stirred at 80° C. for 3 h in a carbon monoxide atmosphere. Asaturated sodium bicarbonate aqueous solution was poured into thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was then purified by silica gel column chromatography(Yamazen Autopurification Device) to obtain the title compound (18 mg)having the following physical property values.

TLC: Rf 0.38 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 0.99, 1.61-1.80, 1.87, 2.27-2.36, 2.37-2.44, 2.61,2.71, 3.43-3.56, 3.66, 3.81, 4.11-4.23, 4.32-4.42, 6.86, 7.19, 7.27,7.42-7.62, 7.73, 8.73, 9.38.

Example 22:4-[2-({[(2′R,4S)-6-Benzoyl-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)-4-cyanophenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 26, instead of the compound produced inReference Example 12.

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.53-1.64, 1.64-1.78, 2.10-2.30, 2.41-2.75,3.20-3.49, 4.10-4.23, 4.33-4.45, 6.94, 7.36-7.45, 7.46-7.59, 7.60-7.73,7.87, 9.89, 12.09.

Example 23

The present compounds having the following physical property values wereproduced by performing the same procedures from Reference Example 26 toExample 1, except that the phenylboronic acid was replaced with acorrespond boronic acid.

Example 23-1: 4-[4-Cyano-2-({[(2′R,4S)-6-(cyclopropylcarbonyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.41 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.02-1.38, 1.67-1.83, 2.06-2.38, 2.45-2.78, 4.33-4.45,4.53-4.67, 6.89, 7.19, 7.25-7.30, 7.87, 7.98, 8.88, 9.85.

Example 23-2:4-[2-({[(2′R,4S)-6-Acetyl-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)-4-cyanophenyl]butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.20-1.31, 1.70-1.85, 2.05-2.20, 2.23-2.33, 2.44-2.83,4.33-4.45, 4.53-4.65, 6.85, 7.20, 7.28, 7.70, 8.06, 8.89, 9.83.

Reference Example 27: Ethyl4-(4-cyano-2-{[(2′R,4S)-6-(methanesulfonyl)-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carbonyl]amino}phenyl)butanoate

In an argon atmosphere, sodium hydroxide (2.3 mg) was added to a 2-mLDMSO solution of L-proline (7 mg), and the mixture was stirred at roomtemperature for 30 min. To the reaction mixture were added the compound(40 mg) produced in Reference Example 10, copper iodide (11 mg), andsodium methanesulfinate (37 mg), and the mixture was stirred at 100° C.for 1 h using a microwave reactor (Biotage, Ltd.). The reaction mixturewas then purified by silica gel column chromatography (YamazenAutopurification Device) to obtain the title compound (33 mg) having thefollowing physical property values.

TLC: Rf 0.58 (hexane:ethyl acetate=1:3);

¹H-NMR (CDCl₃): δ 1.13, 1.66-1.80, 1.91, 2.20-2.45, 2.53-2.64, 2.67,3.01, 3.45-3.60, 3.73-3.86, 4.11-4.20, 4.40, 6.96, 7.20, 7.30, 7.40,7.63, 8.71, 9.44.

Example 24:4-[4-Cyano-2-({[(2′R,4S)-6-(methylsulfonyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 27, instead of the compound produced inReference Example 12.

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.53-1.64, 1.72, 1.80-1.87, 2.08-2.29, 2.35-2.74,3.18, 4.05-4.20, 4.32-4.44, 7.02, 7.40, 7.42, 7.57, 7.64, 7.87, 9.95,12.10.

Example 25: 4-[4-Cyano-2-({[(2′R,4S)-6-(cyclopropylsulfonyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures from Reference Example 27 toExample 1, using sodium cyclopropanesulfinate instead of sodiummethanesulfinate.

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.00-1.15, 1.20-1.43, 1.60-1.82, 2.09-2.35, 2.38-2.60,2.63-2.75, 3.39, 4.35, 4.57, 6.95, 7.20, 7.29, 7.59, 7.71, 8.90, 9.64.

Reference Example 28:(2′R,4S)-7-(Benzyloxy)-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carboxylicacid

The title compound having the following physical property values wasobtained by performing the procedures of Reference Example 1→ReferenceExample 2→Reference Example 3, using7-(benzyloxy)-2,3-dihydro-4H-chromen-4-one instead of 4-chromanone.

TLC: Rf 0.21 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.53-1.70, 2.07, 2.20, 4.20-4.09, 4.23-4.33, 5.01,6.46, 6.52, 6.60, 7.27-7.44.

HPLC retention time: 12.2 min (CHIRALPAK IC 4.6 mm×250 mm hexane:ethylacetate:formic acid=97:3:1).

Reference Example 29: Ethyl4-(2-{[(2′R,4S)-7-(benzyloxy)-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carbonyl]amino}-4-cyanophenyl)butanoate

The title compound having the following physical property values wasobtained by performing the procedures of Reference Example 10 using thecompound produced in Reference Example 28, instead of the compoundproduced in Reference Example 6.

¹H-NMR (CDCl₃): δ 1.13, 1.54-1.61, 1.64-1.81, 2.22, 2.37-2.45,2.51-2.66, 3.55-3.68, 3.72-3.86, 4.03, 4.16, 4.22-4.32, 4.99, 6.42-6.51,6.73, 7.18, 7.28, 7.29-7.44, 8.72, 9.28.

Example 26:4-[2-({[(2′R,4S)-7-(Benzyloxy)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)-4-cyanophenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1 using the compoundproduced in Reference Example 29, instead of the compound produced inReference Example 12.

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.58, 1.68-1.84, 2.10-2.20, 2.36, 2.46, 2.50-2.75,4.03-4.16, 4.20-4.32, 5.02, 6.48, 6.54, 6.71, 7.20, 7.27-7.45, 8.54,8.82.

Reference Example 30: Ethyl4-(4-cyano-2-{[(2′R,4S)-7-hydroxy-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carbonyl]amino}phenyl)butanoate

ASCA-2 (trade name; 50% wet, 300 mg) was added to a mixed solution ofthe compound (650 mg) produced in Reference Example 29 in ethanol (50mL) and ethyl acetate (10 mL), and the mixture was stirred at roomtemperature for 8 h in a hydrogen atmosphere. The reaction mixture wasfiltered using Celite (trade name), and the filtrate was concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (Yamazen Autopurification Device), and washed witha tert-butyl methyl ether and hexane to obtain the title compound (368mg) having the following physical property values.

TLC: Rf 0.28 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.16, 1.55-1.62, 1.66-1.80, 2.16-2.25, 2.38-2.47,2.52-2.66, 3.60-3.73, 3.76-3.87, 4.04-4.15, 4.22-4.32, 4.63, 6.28-6.37,6.69, 7.18, 7.28, 8.71, 9.28.

Example 27:4-[4-Cyano-2-({[(2′R,4S)-7-(3-pyridinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Reference Example 23→ReferenceExample 15→Example 1 using the compound produced in Reference Example 30instead of the compound produced in Reference Example 20, usingpyridine-3-boronic acid instead of 4-fluorophenylboronic acid.

TLC: Rf 0.39 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.55-1.63, 1.65-1.80, 2.09-2.18, 2.21, 2.40-2.47,2.53-2.77, 4.04-4.16, 4.28-4.38, 7.05, 7.15, 7.25, 7.41, 7.43-7.50,7.57, 7.88, 8.02-8.08, 8.55, 8.85, 9.90, 12.10.

Example 28

The present compounds having the following physical property values wereobtained by performing the procedures of Reference Example 23→ReferenceExample 24→Reference Example 12→Example 1 using the compound produced inReference Example 30 instead of the compound produced in ReferenceExample 20, using methylamine hydrochloride or 2-methoxyethylamine.

Example 28-1:4-[4-Cyano-2-({[(2′R,4S)-7-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.56, 1.63-1.80, 2.02-2.15, 2.20, 2.42, 2.57-2.69,2.74, 4.01-4.13, 4.23-4.37, 6.99, 7.24, 7.36, 7.40, 7.56, 7.86, 8.34,9.89, 12.11.

Example 28-2:4-{4-Cyano-2-[({(2′R,4S)-7-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.63-1.89, 2.00-2.13, 2.25-2.47, 2.48-2.73, 2.78-2.93,3.24-3.39, 3.51, 3.55-3.65, 3.85-4.06, 6.68, 6.79, 7.06, 7.20, 7.29,7.98, 8.78, 9.84.

Example 29: 4-[2-({[(2′R,4S)-6-(Benzyloxy)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)-4-cyanophenyl]butanoic acid

The present compound having the following physical property values wasobtained by performing the procedures of Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4→Reference Example6→Reference Example 10→Example 1, using6-(benzyloxy)-3,4-dihydro-2H-1-benzopyran-4-one instead of 4-chromanone.Iodoethane was used instead of iodomethane.

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.46-1.55, 1.62-1.80, 2.12-2.18, 2.43-2.48, 2.51-2.76,4.18-4.26, 4.95-5.07, 6.62, 6.75-6.80, 7.18, 7.28, 7.31-7.45, 8.68,9.14.

Reference Example 31: Ethyl4-(4-cyano-2-{[(2′R,4S)-6-hydroxy-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carbonyl]amino}phenyl)butanoate

The title compound having the following physical property values wasobtained by performing the procedures of Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4→Reference Example6→Reference Example 10→Reference Example 30, using6-(benzyloxy)-3,4-dihydro-2H-1-benzopyran-4-one instead of 4-chromanone.

TLC: Rf 0.66 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 1.16, 1.52-1.58, 1.66-1.83, 2.21, 2.41, 2.55-2.73,3.65-3.78, 3.84-3.98, 4.02-4.13, 4.17-4.27, 4.54, 6.33, 6.55, 6.68,7.19, 7.28, 8.74, 9.38.

Example 30:4-[4-Cyano-2-({[(2′R,4S)-6-hydroxy-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Example 1, using the compoundproduced in Reference Example 31 instead of the compound produced inReference Example 12.

TLC: Rf 0.38 (dichloromethane:methanol=9:1);

¹H-NMR (CD₃OD): δ 1.55-1.70, 1.77-1.90, 2.11-2.20, 2.33, 2.40-2.48,2.67-2.78, 4.04-4.15, 4.17-4.26, 6.28, 6.53, 6.64, 7.41, 7.48, 7.90.

Example 31

The present compounds having the following physical property values wereobtained by performing the procedures from Reference Example 21 toExample 1, using the compound produced in Reference Example 31 insteadof the compound produced in Reference Example 20. 2-Oxazolemethanol ormethanol was used instead of (1-methylpyrazol-4-yl)methanol.

Example 31-1:4-[4-Cyano-2-({[(2′R,4S)-6-(1,3-oxazol-2-ylmethoxy)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

¹H-NMR (CD₃OD): δ 1.58-1.76, 1.77-1.90, 2.09-2.21, 2.33, 2.47, 2.72,4.08-4.17, 4.18-4.29, 5.11, 6.53, 6.70, 6.77, 7.21, 7.42, 7.48, 7.92,7.96.

Example 31-2: 4-(4-Cyano-2-{[(2′R,4S)-6-methoxy-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carbonyl]amino}phenyl)butanoic acid

TLC: Rf 0.35 (ethyl acetate);

¹H-NMR (DMSO-d₆) δ 1.50-1.56, 1.65-1.80, 2.00-2.09, 2.20, 2.35-2.47,2.55-2.60, 2.61-2.69, 2.70-2.75, 3.69, 3.92-4.04, 4.15-4.26, 6.43, 6.71,7.40, 7.56, 7.85, 9.86, 12.11.

Example 32:4-[4-Cyano-2-({[(2′R,4S)-7-(1,3-oxazol-2-ylmethoxy)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures from Reference Example 21 toExample 1, using the compound produced in Reference Example 30 insteadof the compound produced in Reference Example 20. 2-Oxazolemethanol wasused instead of (1-methylpyrazol-4-yl)methanol.

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.58-1.68, 1.68-1.80, 2.03-2.15, 2.18-2.46, 2.41-2.50,2.50-2.63, 2.64-2.83, 4.00-4.13, 4.20-4.31, 5.05, 5.17, 6.33, 6.48,6.63, 7.10, 7.20, 7.28, 7.73, 8.62, 8.91.

Reference Example 32: Ethyl(2′R,4S)-7-methoxy-2,3-dihydrospiro[1-benzopyran-4,1′-cyclopropane]-2′-carboxylate

The procedures of Reference Example 4 were performed using the compoundproduced in Reference Example 28 instead of the compound produced inReference Example 3. Iodoethane was used instead of iodomethane.Palladium hydroxide/carbon (10% wet, 0.2 g) was added to a 5-mL ethylacetate solution of the resulting compound (2.1 g), and the mixture wasstirred at room temperature for 30 min in a hydrogen atmosphere. Thereaction mixture was filtered using Celite (trade name), and thefiltrate was concentrated under reduced pressure. After adding potassiumcarbonate (1.46 g) to a 5-mL DMF solution of the resulting residue (1.31g), iodomethane (1.5 g) was dropped, and the mixture was stirredovernight at room temperature. The reaction mixture was poured into icewater, and extracted with a hexane-ethyl acetate mixed solution. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated under reduced pressure to obtainthe title compound (1.38 g) having the following physical propertyvalues.

TLC: Rf 0.69 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.25, 1.55-1.60, 2.05, 2.13-2.20, 3.75, 4.05-4.20,4.23-4.31, 6.38, 6.45, 6.59.

Example 33

The present compounds having the following physical property values wereobtained by performing the procedures of Reference Example 5→ReferenceExample 6→Reference Example 10→Reference Example 11→Reference Example12→Example 1, using the compound produced in Reference Example 32instead of the compound produced in Reference Example 4, usingmethylamine hydrochloride or a corresponding amine compound.

Example 33-1:4-[4-Cyano-2-({[(2′R,4S)-7-methoxy-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.39 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.42-1.60, 1.65-1.79, 2.00-2.29, 2.32-2.74, 2.77,3.83, 4.05-4.17, 4.24-4.38, 6.54, 7.35-7.45, 7.55, 7.89, 7.98, 9.88,12.12.

Example 33-2:4-{4-Cyano-2-[({(2′R,4S)-7-methoxy-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoicacid

TLC: Rf 0.39 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ1.46-1.60, 1.64-1.81, 2.00-2.29, 2.36-2.76, 3.27,3.38-3.48, 3.85, 4.06-4.18, 4.25-4.36, 6.56, 7.40, 7.41, 7.55, 7.89,8.09, 9.87, 12.10.

Example 33-3:4-[4-Cyano-2-({[(2′R,4S)-6-(ethylcarbamoyl)-7-methoxy-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.54 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ 1.09, 1.47-1.58, 1.65-1.78, 2.04-2.23, 2.47,2.60-2.69, 3.21-3.30, 3.84, 4.11, 4.30, 6.54, 7.35-7.44, 7.56, 7.89,8.04, 9.88, 12.11.

Example 33-4:4-[4-Cyano-2-({[(2′R,4S)-7-methoxy-6-(propylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.70 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ0.87, 1.41-1.58, 1.63-1.76, 2.00-2.23, 2.43,2.59-2.70, 3.13-3.28, 3.84, 4.11, 4.29, 6.55, 7.32-7.42, 7.56, 7.90,8.02, 9.88, 12.11.

Example 33-5:4-[4-Cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-7-methoxy-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.68 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆): δ1.14, 1.46-1.58, 1.63-1.78, 2.01-2.22, 2.46,2.58-2.69, 3.84, 3.97-4.16, 4.31, 6.55, 7.34-7.43, 7.56, 7.74, 7.89,9.87, 12.09.

Example 34:4-[4-Cyano-2-({[(2′R,4S)-7-methoxy-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures of Reference Example 5→ReferenceExample 6→Reference Example 10→Reference Example 11→Reference Example13→Example 1, using the compound produced in Reference Example 32instead of the compound produced in Reference Example 4.

TLC: Rf 0.38 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.16-1.27, 1.50-1.58, 1.66-1.85, 2.09-2.30, 2.42-2.83,3.46, 3.85, 4.35, 4.55, 6.48, 7.19, 7.27, 7.68, 8.88, 9.90.

Example 35:4-[4-Cyano-2-({[(2′R,4S)-6-(4-morpholinyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

Cesium carbonate (129 mg),[(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)chloride (9 mg), and morpholine (34 mg) were added to a 1-mL DMFsolution of the compound (72 mg) produced in Reference Example 10, andthe mixture was stirred at 110° C. for 1 h using a microwave reactor(Biotage, Ltd.). A potassium carbonate aqueous solution was poured intothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(Yamazen Autopurification Device) to obtain an ethyl ester (46 mg). Thepresent compound was obtained by performing the procedures of Example 1using the ethyl ester, instead of the compound produced in ReferenceExample 12.

TLC: Rf 0.36 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.45-1.55, 1.62-1.80, 2.00-2.10, 2.16-2.26,2.32-2.77, 2.89-3.06, 3.65-3.78, 3.90-4.05, 4.13-4.26, 6.39, 6.67, 6.74,7.40, 7.56, 7.84, 9.87, 12.08.

Reference Example 33: Ethyl4-(4-cyano-2-{[(2′R,3S)-5-iodo-2H-spiro[1-benzofuran-3,1′-cyclopropane]-2′-carbonyl]amino}phenyl)butanoate

The title compound having the following physical property values wasobtained by performing the procedures of Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4→Reference Example5→Reference Example 6→Reference Example 10, using 3-coumaranone insteadof 4-chromanone. Iodoethane was used instead of iodomethane.

¹H-NMR (CDCl₃): δ 1.32, 1.57, 1.66-1.82, 2.36-2.70, 2.79, 3.95-4.22,4.70, 6.60, 7.02, 7.20, 7.24-7.32, 7.38, 8.74, 9.40.

Example 36:4-[4-Cyano-2-({[(2′R,3S)-5-(3-pyridinyl)spiro[1-benzofuran-3,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures from Reference Example 15 toExample 1 using the compound produced in Reference Example 33 instead ofthe compound produced in Reference Example 10. Pyridine-3-boronic acidwas used instead of 4-fluorophenylboronic acid.

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ1.06, 1.62-1.92, 2.58, 2.78, 2.94, 4.85, 6.47, 6.87,7.01-7.40, 8.41, 8.61, 8.79, 9.75.

Example 37

The present compounds having the following physical property values wereobtained by performing the procedures of Reference Example 11→ReferenceExample 12→Example 1, using the compound produced in Reference Example33 instead of the compound produced in Reference Example 10, usingmethylamine hydrochloride or 2-methoxyethylamine.

Example 37-1:4-[4-Cyano-2-({[(2′R,3S)-5-(methylcarbamoyl)spiro[1-benzofuran-3,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ1.57, 1.61-1.86, 2.30-2.73, 3.02, 3.22, 4.59, 4.73,6.18, 6.76, 7.18, 7.20-7.32, 7.59, 8.70, 9.51.

Example 37-2:4-{4-Cyano-2-[({(2′R,3S)-5-[(2-methoxyethyl)carbamoyl]spiro[1-benzofuran-3,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid

TLC: Rf 0.57 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.58, 1.60-1.85, 2.30-2.75, 3.19, 3.41, 3.50-3.73,4.61, 4.74, 6.47-6.62, 6.77, 7.19, 7.21-7.40, 7.56, 8.72, 9.47.

Reference Example 34: 6-Iodo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one

A sodium nitrite aqueous solution (4.5 mol/L, 4 mL) was dropped into ahydrochloric acid aqueous solution (5 mol/L, 15 mL) of6-amino-3,3-dimethyl-indan-1-one (2.1 g) on ice, and the mixture wasstirred for 30 min. After confirming the disappearance of the rawmaterials, a potassium iodide aqueous solution (4 mol/L, 6 mL) wasdropped into the mixture on ice. The mixture was then stirred at roomtemperature for 1 h after adding acetonitrile (20 mL). A saturatedsodium bicarbonate aqueous solution was added to the reaction mixture onice, and the mixture was extracted with ethyl acetate. The organic layerwas washed with a saturated sodium thiosulfate aqueous solution, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The resulting residue was then purified by silica gel columnchromatography to obtain the title compound (2.66 g) having thefollowing physical property values.

TLC: Rf 0.86 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.38-1.44, 2.59, 7.25-7.30, 7.90, 8.03.

Reference Example 35: Ethyl4-(4-cyano-2-{[(1S,2R)-6′-iodo-3′,3′-dimethyl-2′,3′-dihydrospiro[cyclopropane-1,1′-indene]-2-carbonyl]amino}phenyl)butanoate

The title compound having the following physical property values wasobtained by performing the procedures of Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 10, using the compoundproduced in Reference Example 34 instead of 4-chromanone.

¹H-NMR (CDCl₃): δ1.14-1.35, 1.44, 1.64-1.79, 1.79-1.88, 2.17, 2.28-2.50,2.50-2.71, 3.83, 4.05, 6.91, 7.11, 7.19, 7.22-7.31, 7.45-7.53, 8.79,9.28.

Example 38

The present compounds having the following physical property values wereobtained by performing the procedures of Reference Example 11→ReferenceExample 12→Example 1, using the compound produced in Reference Example35 instead of the compound produced in Reference Example 10, usingmethylamine hydrochloride or 2-methoxyethylamine.

Example 38-1:4-[4-Cyano-2-({[(1S,2R)-6′-[(2-methoxyethyl)carbamoyl]-3′,3′-dimethyl-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.64 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.28-1.40, 1.72, 1.86, 2.01-2.10, 2.14-2.23, 2.63,3.16, 3.40, 3.53-3.81, 6.64, 7.17, 7.22-7.31, 7.33-7.44, 7.70, 8.82,9.51.

Example 38-2:4-[4-Cyano-2-({[(1S,2R)-3′,3′-dimethyl-6′-(methylcarbamoyl)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoicacid

TLC: Rf 0.55 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.29-1.42, 1.63-1.80 1.83-1.90, 1.98-2.11, 2.11-2.24,2.32-2.56, 2.57-2.69, 3.04, 3.19, 6.24, 7.11-7.19, 7.21-7.34, 7.72,8.82, 9.57.

Example 39:4-[4-Cyano-2-({[(1S,2R)-3′,3′-dimethyl-6′-(3-pyridinyl)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2-yl]carbonyl}amino)phenyl]butanoicacid

The present compound having the following physical property values wasobtained by performing the procedures from Reference Example 15 toExample 1 using the compound produced in Reference Example 35 instead ofthe compound produced in Reference Example 10. Pyridine-3-boronic acidwas used instead of 4-fluorophenylboronic acid.

TLC: Rf 0.62 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 0.59, 1.27-1.43, 1.55-1.69, 1.79, 2.18-2.38,2.52-2.64, 2.64-2.91, 6.53, 7.16-7.35, 7.54, 8.39-8.50, 8.75-8.84, 9.35.

PHARMACOLOGICAL EXPERIMENT EXAMPLES Pharmacological Experiment Example1: EP₄ Antagonistic Activity Measurement Experiment Using ProstanoidReceptor Subtype Expressing Cells

CHO cells expressing rat EP₄ receptor subtypes were prepared accordingto the methods of Nishigaki et al. (FEBS Letters, Vol. 364, p. 339-341,1995), and used for experiment. Cultured subconfluent cells weredetached, and suspended in an assay medium (MEM containing 1 mmol/LIBMX, 1% HSA) in a concentration of 1×10⁶ cells/mL. For reaction, PGE₂was added to the cell suspension (25 μL) in a final concentration of 10nmol/L, either alone or as a 25-μL PGE₂ solution containing the testcompound. After 30 minutes of reaction at room temperature, the amountof cAMP in the cells was quantified according to the method in thedescriptions of the cAMP assay kit (CISBIO).

The antagonistic effect (IC₅₀ value) of the test compound was calculatedas a value that represents an inhibition rate against a reaction withPGE₂ alone at 10 nM, a concentration that produces a submaximal cAMPproducing effect.

The present compounds were shown to have strong EP₄ receptorantagonistic activity. As examples, Table 1 below shows the IC₅₀ valuesof some of the present compounds. The EP₄ receptor antagonistic activitywas very weak, 2,800 nM, for the compound in Example 8-128 ofWO2003/016254.

TABLE 1 EP₄ antagonistic activity Example (IC₅₀, nM) 1 2.5 2-2 5.3 2-33.5 2-4 3.3 2-5 1.3 2-9 4.5  2-10 4.0  2-13 7.8  2-14 4.5  2-23 4.5 2-29 2.5  2-32 3.7  2-33 9.7  2-36 5.4  2-37 3.4  2-38 4.7  2-39 3.4 2-40 7.2  2-41 3.4  2-43 3.6  2-44 2.5  2-45 8.3  2-46 3.0 3 2.7 5 2.87-1 17 7-3 3.8 7-4 2.4  7-10 8.6  7-13 3.5  7-16 5.7  7-17 6.1  7-19 4.5 7-21 10 10-3  5.7 10-4  3.5 10-5  4.1 10-9  6.7 18-1  1.2 18-2  3.018-3  2.7 20-1  8.5 20-2  1.6 20-5  9.5 28-1  6.4 28-2  6.9 33-1  1033-2  8.4 36  4.5 37-1  7.2 37-2  6.2 38-1  5.4 38-2  4.3 39  5.7

Pharmacological Experiment Example 2: Pharmacokinetics Test (HepaticMicrosome Stability Test) (1) Preparation of Subject Substance Solution

A DMSO solution of the subject substance (the present compound, and acomparative compound) (10 mmol/L; 5 μL) was diluted with a 50%acetonitrile aqueous solution (195 μL) to prepare a 250 μmol/L subjectsubstance solution.

(2) Preparation of Standard Sample (Sample Immediately after Reaction)

First, 245 μL of a 0.1 mol/L phosphate buffer (pH 7.4) containing anNADPH-Co-Factor (BD-Bioscience), and 1 mg/mL of human hepatic microsomewas added to a reaction vessel that had been heated to 37° C. with awater bath, and the solution was preincubated for 5 min. To thissolution was added 5 μL of the subject substance solution to start areaction (final concentration of 1 μmol/L). Immediately after thereaction was started, 20 μL of the reaction solution was collected, andadded to 180 μL of acetonitrile (containing candesartan as an internalstandard) to quench the reaction. The quenched solution (20 μL; a samplesolution immediately after the reaction) was stirred with 50%acetonitrile (180 μL) on a deproteinization filter plate, and subjectedto suction filtration. The filtrate was then obtained as a standardsample.

(3) Preparation of Reaction Sample (Sample after 60 Min from Reaction)

The reaction solution was incubated at 37° C. for 60 min, and 20 μL ofthe reaction solution was collected, and added to 180 μL of acetonitrile(containing candesartan as an internal standard) to quench the reaction.The quenched solution (20 μL; a sample solution after 60 minutes ofreaction) was stirred with 50% acetonitrile (180 μL) on adeproteinization filter plate, and subjected to suction filtration. Thefiltrate was then obtained as a reaction sample.

(4) Evaluation Method

Using peak areas from LC-MS/MS, the subject substance remaining rate (%)was calculated from the mass (X) of the subject substance in thestandard sample, and the mass (Y) of the subject substance in thereaction sample, according to the following formula.

Remaining rate (%)=(Y/X)×100

X: Mass of the subject substance in standard sample (ratio=peak area ofsubject substance/peak area of internal standard)

Y: Mass of the subject substance in reaction sample (ratio=peak area ofsubject substance/peak area of internal standard)

(5) Result

The present compounds were shown to have high stability against humanhepatic microsome (high remaining rate (%)). As examples, Table 2 belowshows the remaining rates of some of the present compounds. Theremaining rate was 35% for the compound in Example 6-117 ofWO2003/016254.

TABLE 2 Remaining Example rate (%) 1 94 2-2 97 2-3 91 2-4 86 2-5 93 2-992  2-10 94  2-13 100  2-14 96  2-23 100  2-29 80  2-32 85  2-33 89 2-36 100  2-37 97  2-38 100  2-39 90  2-40 100  2-41 100  2-43 100 2-44 100  2-45 100  2-46 90 3 100 5 80 7-1 81 7-3 72 7-4 71  7-10 89 7-13 95  7-16 80  7-17 82  7-19 100  7-21 76 10-3  87 10-4  73 10-5  8610-9  75 18-1  90 18-2  100 18-3  91 20-1  88 20-2  77 20-5  100 28-1 91 28-2  100 33-1  98 33-2  100 36  93 37-1  77 37-2  87 38-1  69 38-2 89 39  78

Pharmacological Experiment Example 3: Anti-Tumor Effect in AllograftModel of Mouse Colorectal Cancer Cell Line CT26

The anti-tumor effect of the present compound was evaluated in anallograft model of the mouse colorectal cancer cell line CT26. CT26 wascultured in a CO₂ incubator, using an RPMI-1640 medium containing 10 vol% inactivated fetal bovine serum (FBS), 100 units/mL of penicillin, and100 μg/mL of streptomycin. On the day of transplant, CT26 was harvestedafter removing the culture supernatant, and washing the cells withphosphate buffer (hereinafter, “PBS”). The harvested CT26 cells weresuspended in Hank's buffer to obtain transplant cells. The transplantcells (3×10⁵) were then subcutaneously transplanted to the right back ofa female Balb/C mouse (Charles River Laboratories Japan Inc.) underanesthesia. The present compound was orally administered in a dose of 10mg/kg, once on the day of transplant, and twice a day from the next day.For the control group, distilled water was administered for the sameduration as in the present compound-administered group. The tumor volume(mm³) was determined by calculating a relative tumor volume from themeasured tumor lengths along the minor axis and major axis using adigital caliper, according to the following formulae 1 and 2.

Tumor volume=[(minor axis)²×major axis]/2

Relative tumor volume=medium value of tumor volumes of each group after21 days from transplant/medium value of tumor volume of control groupafter 21 days from transplant

The present compounds had a tumor growth inhibitory effect. As examples,FIG. 1 shows the relative tumor volumes for Examples 2-2 and 2-13.

PREPARATION EXAMPLES Preparation Example 1

The following components were mixed and punched using an ordinary methodto obtain 10,000 tablets containing 10 mg of the active component pertablet.

4-[4-Cyano-2-({[(2′R,4S)-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid: 100 g

Carboxymethyl cellulose calcium (disintegrator): 20 g

Magnesium stearate (lubricant): 10 g

Microcrystalline cellulose: 870 g

Preparation Example 2

The following components were mixed using an ordinary method, andfiltered through a dust filter. The preparation was charged into ampulesin 5-ml portions, and heat sterilized with an autoclave to obtain 10,000ampules containing 20 mg of the active component per ampule.

4-[4-Cyano-2-({[(2′R,4S)-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid: 200 g

Mannitol: 20 g

Distilled water: 50 L

INDUSTRIAL APPLICABILITY

The present compound has antagonistic activity against the EP₄ receptor,and is effective for the prevention and/or treatment of diseases causedby EP₄ receptor activation.

What is claimed is:
 1. A pharmaceutical composition comprising acompound that is4-[4-cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid, a salt thereof, or a solvate thereof as an active ingredient. 2.The pharmaceutical composition according to claim 1, which is an EP₄receptor antagonist.
 3. The pharmaceutical composition according toclaim 1, which is a preventive and/or a therapeutic agent against adisease caused by EP₄ receptor activation.
 4. The pharmaceuticalcomposition according to claim 3, wherein the disease caused by EP₄receptor activation is a bone disease, a cancer, a systemicgranulomatous disease, an immune disease, alveolar pyorrhea, gingivitis,periodontitis, Kawasaki disease, multiple organ failure, chronicheadache, pain, vasculitis, venous incompetence, varicose veins,aneurysm, aortic aneurysm, anal fistula, diabetes insipidus, patentductus arteriosus in neonates, or cholelithiasis.
 5. The pharmaceuticalcomposition according to claim 4, wherein the cancer is breast cancer,ovarian cancer, colorectal cancer, lung cancer, prostate cancer, headand neck cancer, lymphoma, uveal melanoma, thymoma, mesothelioma,esophageal cancer, stomach cancer, duodenal cancer, hepatocellularcarcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic cancer,renal cell carcinoma, renal pelvis and ureter cancer, bladder cancer,penile cancer, testicular cancer, uterus cancer, vaginal cancer, vulvarcancer, skin cancer, malignant bone tumor, soft tissue sarcoma,chondrosarcoma, leukemia, myelodysplastic syndrome, or multiple myeloma.6. A medicament comprising: a compound that is4-[4-cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid, a salt thereof, or a solvate thereof; and at least one selectedfrom the group consisting of an alkylating agent, an antimetabolite, ananti-cancer antibiotic, a plant-based preparation, a hormonal agent, aplatinum compound, a topoisomerase inhibitor, a kinase inhibitor, ananti-CD20 antibody, an anti-HER2 antibody, an anti-EGFR antibody, ananti-VEGF antibody, a proteasome inhibitor, an HDAC inhibitor, and animmunomodulator.
 7. A method for preventing and/or treating a diseasecaused by EP₄ receptor activation, the method comprising administeringan effective amount of a compound that is4-[4-cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoicacid, a salt thereof, or a solvate thereof to a patient in need thereof.8. The method according to claim 7, wherein the disease caused by EP₄receptor activation is a bone disease, a cancer, a systemicgranulomatous disease, an immune disease, alveolar pyorrhea, gingivitis,periodontitis, Kawasaki disease, multiple organ failure, chronicheadache, pain, vasculitis, venous incompetence, varicose veins,aneurysm, aortic aneurysm, anal fistula, diabetes insipidus, patentductus arteriosus in neonates, or cholelithiasis.
 9. The methodaccording to claim 8, wherein the cancer is breast cancer, ovariancancer, colorectal cancer, lung cancer, prostate cancer, head and neckcancer, lymphoma, uveal melanoma, thymoma, mesothelioma, esophagealcancer, stomach cancer, duodenal cancer, hepatocellular carcinoma,cholangiocarcinoma, gallbladder cancer, pancreatic cancer, renal cellcarcinoma, renal pelvis and ureter cancer, bladder cancer, penilecancer, testicular cancer, uterus cancer, vaginal cancer, vulvar cancer,skin cancer, malignant bone tumor, soft tissue sarcoma, chondrosarcoma,leukemia, myelodysplastic syndrome, or multiple myeloma.
 10. The methodaccording to claim 7, further comprising administering at least oneagent selected from the group consisting of an alkylating agent, anantimetabolite, an anti-cancer antibiotic, a plant-based preparation, ahormonal agent, a platinum compound, a topoisomerase inhibitor, a kinaseinhibitor, an anti-CD20 antibody, an anti-HER2 antibody, an anti-EGFRantibody, an anti-VEGF antibody, a proteasome inhibitor, a HDACinhibitor, and an immunomodulator.
 11. The method according to claim 7,wherein a dosage form for the administration is at least one selectedfrom the group consisting of an oral preparation, an oro-mucosalpreparation, a preparation for injection, a preparation for dialysis, apreparation for inhalation, a preparation for ophthalmic application, apreparation for otic application, a preparation for nasal application, apreparation for rectal application, a preparation for vaginalapplication, and a preparation for cutaneous application.